Pyrrolopyridazine compounds and methods of use thereof for the treatment of proliferative disorders

ABSTRACT

Disclosed are pyrrolopyridazine compounds of the formula, 
                 
 
wherein the substituents are defined herein,
 
methods of preparing such compounds, and their use for the treatment of proliferative, inflammatory, and other disorders.

RELATED APPLICATIONS

This application is continuation-in-part of U.S. Non-ProvisionalApplication No. 10/396,197, filed Mar. 25, 2003, the contents of whichare herein incorporated by reference and benefit of which is claimed.

FIELD OF THE INVENTION

The present invention relates to pyrrolopyridazine compounds, methods ofpreparing such compounds, and their use for the treatment ofpoliferative and other disorders.

BACKGROUND OF THE INVENTION

protein kinases are a class of enzymes that catalyze the transfer of aphosphate group from ATP to a tyrosine, serine, threonine, or histidineresidue located on a protein substrate. Protein kinases clearly play arole in normal cell growth. Many of the growth factor receptor proteinshave intracellular domains that function as protein kinases and it isthrough this function that they effect signaling. The interaction ofgrowth factors with their receptors is a necessary event in the normalregulation of cell growth, and the phosphorylation state of substrateproteins often is related to the modulation of cell growth.

The human epidermal growth factor receptor (HER) family consists of fourdistinct receptor tyrosine kinases referred to as HER1, HER2, HER3, andHER4. These kinases are also referred to as erbB1, erbB2, etc. HER1 isalso commonly referred to as the epidermal growth factor receptor(EGFr). With the exception of HER3, these receptors have intrinsicprotein kinase activity that is specific for tyrosine residues ofphosphoacceptor proteins. The HER kinases are expressed in mostepithelial cells as well as tumor cells of epithelial origin. They arealso often expressed in tumor cells of mesenchymal origin such assarcomas or rhabdomyosarcomas. Receptor tyrosine kinases (RTKs) such asHER1 and HER2 are involved in cell proliferation and are associated withdiseases such as psoriasis and cancer. Disruption of signal transductionby inhibition of these kinases in target cells is known to have anantiproliferative and therapeutic effect.

The enzymatic activity of receptor tyrosine kinases can be stimulated byeither overexpression, or by ligand-mediated dimerization. The formationof homodimers as well as heterodimers has been demonstrated for the HERreceptor family. An example of homodimerization is the dimerization ofHER1 (EGF receptor) by one of the EGF family of ligands (which includesEGF, transforming growth factor alpha, betacellulin, heparin-bindingEGF, and epiregulin). Heterodimerization among the four HER receptorkinases can be promoted by binding to members of the heregulin (alsoreferred to neuregulin) family of ligands. Such heterodimerization,involving HER2 and HER3, or a HER3/HER4 combination, results in asignificant stimulation of the tyrosine kinase activity of the receptordimers even though one of the receptors (HER3) is enzymatically inert.The kinase activity of HER2 has also been shown to be activated byvirtue of overexpression of the receptor alone in a variety of celltypes. Activation of receptor homodimers and heterodimers results inphosphorylation of tyrosine residues on the receptors and on otherintracellular proteins. This is followed by the activation ofintracellular signaling pathways such as those involving the microtubuleassociated protein kinase (MAP kinase) and the phophatidylinositol3-kinase (P13 kinase). Activation of these pathways has been shown tolead to cellular proliferation and the inhibition of apoptosis.Inhibition of HER kinase signaling has been shown to inhibit cellproliferation and survival.

Deregulation of EGF receptors plays a role in the aberrant growth ofepithelial cysts in the disease described as polycystic kidney disease[Du, J., Wilson, P. D., Amer. J. Physiol., 269 (2 Pt 1), 487 (1995);Nauta, J., et al., Pediatric Research, 37(6), 755 (1995); Gattone, V. H.et al., Developmental Biology, 169(2), 504 (1995); Wilson, P. D. et al.,Eur. J. Cell Biol., 61(1), 131, (1993)]. The compounds of thisinvention, which inhibit the catalytic function of the EGF receptors,are consequently useful for the treatment of this disease.

The mitogen-activated protein kinase (MAPK) pathway is a major pathwayin the cellular signal transduction cascade from growth factors to thecell nucleus. The pathway involves kinases at two levels: MAP kinasekinases (MAPKK), and their substances MAP (mitogen activated protein)kinases (MAPK). There are different isoforms in the MAP kinase family.[For review, see Seger, R.; Krebs, E. G. FASEB, 9, 726, (1995)]. Thecompounds of this invention can inhibit the action of one or both ofthese kinases: MEK, a MAP kinase kinase, and its substrate ERK, a MAPkinase. ERK(extracellular regulated kinases), a p42 MAPK, is found to beessential for cell proliferation and differentiation. Over expressionand/or over activation of MEK or ERK has been found to be associatedwith various human cancers [For example, Sivaraman, V. S. et al., C.C.J.Clin. Invest., 99, 1478 (1997)]. It has been demonstrated thatinhibition of MEK prevents activation of ERK and subsequent activationof ERK substrates in cells, resulting in inhibition of cell growthstimulation and reversal of the phenotype of ras-transformed cells[Dudley, D. T. et al., Proc. Nat. Acad. Sci., 92, 7686 (1995)].

Members of the raf family of kinases phosphorylate serine residues onMEK. There are three serine/threonine kinase members of the raf familyknown as a-raf, b-raf, and c-raf. While mutations in the raf genes arerare in human cancers, c-raf is activated by the ras oncogene which ismutated in a wide number of human tumors. Therefore, inhibition of thekinase activity of c-raf may provide a way to prevent ras mediated tumorgrowth [Campbell, S. L., Oncogene, 17, 1395 (1998)].

The Src family of cytoplasmic protein tyrosine kinases consists of atleast eight members (Src, Fyn, Lyn, Yes, Lck, Fgr, Hck and Blk) thatparticipate in a variety of signaling pathways [Schwartzberg, P. L.,Oncogene, 17, 1463 (1998)]. The prototypical member of this tyrosinekinase family is p60^(Src) (Src). Src is involved in proliferation andmigration responses in many cell types. In limited studies, Src activityhas been shown to be elevated in breast, colon (˜90%), pancreatic (>90%)and liver (>90%) tumors. Greatly increased Src activity is alsoassociated with metastasis (>90%) and poor prognosis. Antisense Srcmessage impedes growth of colon tumor cells in nude mice [Staley et al.,Cell Growth & Differentation, 8, 269 (1997)], suggesting that Srcinhibitors should slow tumor growth. In addition to its role in cellproliferation, Src also acts in stress response pathways, including thehypoxia response. Previous studies have shown that colonic tumor cellsgenetically engineered to express antisense Src message form tumorsdemonstrating reduced vascularization in nude mouse models [Ellis, etal., J. Biol. Chem., 273, 1052 (1998)], suggesting that Src inhibitorswould be anti-angiogenic as well as anti-proliferative.

Apart from its role in cancer, Src also appears to play a role inosteoporosis. Mice genetically engineered to be deficient in srcproduction were found to exhibit osteopetrosis, the failure to resorbbone [Soriano, P., Cell, 64, 693 (1991); Boyce, B. F., J. Clin. Invest.,90, 1622 (1992)]. This defect was characterized by a lack of osteoclastactivity. Since osteoclasts normally express high levels of Src,inhibition of Src kinase activity may be useful in the treatment ofosteoporosis [Missbach, M., Bone, 24, 437 (1999)].

In addition to EGFr, there are several other RTKs including FGFr, thereceptor for fibroblast growth factor (FGF); flk-1, also known as KDR,and flt-1, the receptors for vascular endothelial growth factor (VEGF);and PDGFr, the receptor for platelet derived growth factor (PDGF). Theformation of new blood vessels, a process known as angiogenesis, isessential for tumor growth. Two natural angiogenesis inhibitors,angiostatin and endostatin, dramatically inhibited the growth of avariety of solid tumors. [O'Reilly, M. S., Cell, 79, 315 (1994);O'Reilly, M. S., Nature Medicine, 2, 689 (1996); O'Reilly, M. S., Cell,88, 277 (1997)]. Since FGF and VEGF are known to stimulate angiogenesis,inhibition of the kinase activity of their receptors should block theangiogenic effects of these growth factors. In addition, the receptortyrosine kinases tie-1 and tie-2 also play a key role in angiogenesis[Sato, T. N., Nature, 376, 70 (1995)]. Compounds that inhibit the kinaseactivity of FGFr, flk-1, flt-1, tie-1 or tie-2 may inhibit tumor growthby their effect on angiogenesis.

PDGF is a potent growth factor and chemoattractant for smooth musclecells (SMCs), and the renarrowing of coronary arteries followingangioplasty is due in part to the enhanced proliferation of SMCs inresponse to increased levels of PDGF. Therefore, compounds that inhibitthe kinase activity of PDGFr may be useful in the treatment ofrestenosis. In addition, since PDGF and PDGFr are overexpressed inseveral types of human gliomas, small molecules capable of suppressingPDGFr activity have potential utility as anticancer therapeutics[Nister, M., J. Biol. Chem., 266, 16755 (1991); Strawn, L. M., J. Biol.Chem. 269, 21215 (1994)].

In addition, a large number of cytokines participate in the inflammatoryresponse, including IL-1, IL-6, IL-8 and TNF-α. Overproduction ofcytokines such as IL-1 and TNF-α are implicated in a wide variety ofdiseases, including inflammatory bowel disease, rheumatoid arthritis,psoriasis, multiple sclerosis, endotoxin shock, osteoporosis,Alzheimer's disease, and congestive heart failure, among others [Henryet al., Drugs Fut., 24:1345-1354 (1999); Salituro et al., Curr. Med.Chem., 6:807-823 (1999)]. Evidence in human patients indicates thatprotein antagonists of cytokines are effective in treating chronicinflammatory diseases, such as monoclonal antibody to TNF-α (Enbrel)[Rankin et al., Br. J. Rheumatol., 34:334-342 (1995)], and soluble TNF-αreceptor-Fc fusion protein (Etanercept) [Moreland et al., Ann. Intern.Med., 130:478-486 (1999)].

The biosynthesis of TNF-α occurs in many cell types in response to anexternal stimulus, such as a mitogen, an infectious organism, or trauma.Important mediators of TNF-α production are the mitogen-activatedprotein (MAP) kinases, and in particular, p38 kinase. These kinases areactivated in response to various stress stimuli, including but notlimited to proinflammatory cytokines, endotoxin, ultraviolet light, andosmotic shock. Activation of p38 requires dual phosphorylation byupstream MAP kinase kinases (MKK3 and MKK6) on threonine and tyrosinewithin a Thr-Gly-Tyr motif characteristic of p38 isozymes.

There are four known isoforms of p38, i.e., p38-α, p38β, p38γ, and p38δ.The α and β isoforms are expressed in inflammatory cells and are keymediators of TNF-α production. Inhibiting the p38α and β enzymes incells results in reduced levels of TNF-α expression. Also, administeringp38α and β inhibitors in animal models of inflammatory disease hasproven that such inhibitors are effective in treating those diseases.Accordingly, the p38 enzymes serve an important role in inflammatoryprocesses mediated by IL-1 and TNF-α. Compounds that reportedly inhibitp38 kinase and cytokines such as IL-1 and TNF-α for use in treatinginflammatory diseases are disclosed in the following publishedinternational patent applications: WO 00/12497 (quinazoline derivativesas p38 kinase inhibitors); WO 00/56738 (pyridine and pyrimidinederivatives for the same purpose); WO 00/12497 (discusses therelationship between p38 kinase inhibitors); and WO 00/12074 (piperazineand piperidine compounds useful as p38 inhibitors).

In summary, the tight regulation of signal transduction normally exertedby the array of kinase enzymes is often lost in malignant cells.Compounds which modulate these kinases are thus highly desirable for thetreatment of disorders associated with aberrant cellular proliferation.Moreover, compounds which modulate the cytokines associated with theinflammatory response are highly desirable for the treatment ofinflammatory disorders.

SUMMARY OF THE INVENTION

Advantageously, the present invention provides compositions and methodsfor the treatment of proliferative disorders, including cancer, andinflammatory diseases. The methods comprise administering atherapeutically effective amount of a kinase inhibitor of formula I,below, or a salt, solvate, prodrug or stereoisomer thereof, and,optionally, at least one additional therapeutic agent. The treatment ispreferably administered to a mammalian species, more preferably to ahuman, in need thereof.

More specifically, the instant invention provides a compound of formulaI:

including enantiomers, diastereomers, pharmaceutically acceptable salts,prodrugs, and solvates thereof, wherein:

R₁ is selected from the group consisting of H, hydroxyl, alkyl, amino,aralkyl, halogen, —R₁′, —C(O)R₁′, —C(O)OR₁′, —C(O)NR₁′R₁″, —S(O)₂R₁′″,—S(O)₂NR₁′R₁″, OR₁′, OC(O)R₁′, OC(O)OR₁′, OC(O)NR₁′R₁″, OS(O)₂R₁′″, andOS(O)₂NR₁′R₁″;

R₁′ and R₁″ are each independently selected from the group consisting ofH, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, aralkyl, amino,heterocyclo, cycloalkyl and alkylamidinyl groups; R₁′ and R₁″ may alsobe taken together to form one of a cycloalkyl, an aryl, and aheterocyclic group;

R₁′″ is selected from the group consisting of H, alkyl, aryl, aralkyl,heterocyclo, and cycloalkyl;

R₂ is selected from the group consisting of H, alkyl, cycloalkyl, aryl,heterocycle, aralkyl, R₁′OC(O)—, R₁′C(O)NR₁″, R₁′C(O)—, R₁′C(S)—,R₁″R₁′NC(O)—, R₁′R₁′CN—, R₁′N═C—R₁′″O(O)₂S, R₁′R₁″N(O)₂S andR₁′″(O)_(n)S; wherein n is the integer 1 or 2;

R₁ and R₂ may be taken together to form a cycloalkyl, aryl, orheterocyclic group;

X is selected from the group consisting of a valence bond, —CH₂—, O,—CO, —C(O)₂, S, S(O)_(m) and NR₂′; wherein m is 0, 1 or 2; and R₂′ isselected from the group consisting of H, alkyl, aralkyl, C(O)R₁,C(O)OR₁, SO₂NR₁′R₁″, C(O)NR₁′R₁″ and SO₂ R₁′″; with the proviso thatwhen X is S, R₂ is selected from the group consisting of H, alkyl,cycloalkyl, aryl, heterocycle and aralkyl;

R₃ is selected from the group consisting of H, hydroxyl, alkyl,cycloalkyl, heterocycle, aryl, aralkyl, acyl, carbalkoxy, carboxamido,halogen, amine, substituted amine, OR₃′, CH₂OR₃′, CH₂NR₃′R₃″, CH₂SR₃′,OC(O)R₃′, OC(O)R₃′, OC(O)OR₃″, OC(O)NR₃′R₃″, OS(O)₂R₃′, andOS(O)₂NR₃′R₃″; wherein R₃′ and R₃″ are each independently selected fromthe group consisting of H, alkyl, aralkyl, heterocycle, cycloalkyl, andaryl; R₃′ and R₃″ may also be taken together to form a cycloalkyl, aryl,or heterocyclic group; when R₃ is a carbalkoxy, acyl, or carboxamidogroup, these groups are optionally substituted with one or twosubstituent groups, said substituent groups are independently selectedfrom the group consisting of H, alkyl, aralkyl, heterocycle, cycloalkyl,and aryl; said substituent groups may also be taken together to form acycloalkyl, aryl, or heterocyclic group;

R₂ and R₃ may also be taken together to form a cycloalkyl, aryl, orheterocyclic group;

R₄ is selected from the group consisting of H, alkyl, cycloalkyl, aryl,heterocycle, aralkyl, R₁′OC(O), R₁′C(O), R₁″R₁′NC(O), R₁′″O(O)₂S,R₁′R₁″N(O)₂S and R₁′″(O)_(n)S, wherein n is the integer 1 or 2;

Y is selected from the group consisting of a valence bond, O, S,S(O)_(m) and NR₄′; wherein m is 0, 1 or 2; R₄′ is selected from thegroup consisting of H, alkyl, aralkyl, a heterocycle, C(O)R₁, C(O)OR₁,S(O₂)NR₁′R₁″, C(O)NR₁′R₁″, and S(O₂)R₁; with the proviso that when Y isS, R₄ is selected from the group consisting of alkyl, cycloalkyl, aryl,heterocycle and aralkyl; when Y is NR₄′, R₄′ can be taken together withR₃ to form a heterocyclic ring system;

R₅ is selected from the group consisting of H, halogen, cyano, alkyl,cycloalkyl, a heterocycle, aryl, aralkyl, acyl, substituted alkylenegroup, R₁′OC(O), R₁′C(O), R₁″R₁′NC(O), R₁′″O(O)₂S, R₁′R₁″N(O)₂S andR₁′″(O)_(n)S; wherein n the integer 1 or 2;

Z is selected from the group consisting of a valence bond, O,—C(NR⁸)—NR⁹—NR¹⁰R¹¹, S, S(O)_(p) and NR₅′; wherein p is 0, 1 or 2; R₅′is selected from the group consisting of H, alkyl, aralkyl and aheterocycle; with the proviso that when Z is a valence bond, R₅ isselected from the group consisting of H, halogen, a substituted alkylenegroup and a cyano group; and, with the further proviso that when Z is S,R₅ is selected from the group consisting of H, alkyl, cycloalkyl, aryl,heterocycle and aralkyl;

R₆ is selected from the group consisting of H, alkyl, cycloalkyl, aryl,aralkyl, a heterocycle, acyl, carbalkoxy, and carboxamido; saidcarbalkoxy, acyl, and carboxamido groups are optionally substituted withone or two substituent groups, each of which is independently selectedfrom the group consisting of H, alkyl, aralkyl, and a heterocycle; and

R⁸, R⁹, R¹⁰, and R¹¹ are independently H, alkyl, or cycloalkyl.

Further provided are pharmaceutical compositions comprising a compoundof formula I, above, or a salt, solvate, or stereoisomer thereof, and atleast one pharmaceutically acceptable carrier. Optionally, thepharmaceutical composition may also comprise at least one additionaltherapeutic agent.

Also provided are methods of treating proliferative or inflammatorydiseases, in patients in need thereof, by administering a compound offormula I, above, or a salt, solvate, or stereoisomer thereof, and,optionally, at least one additional therapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The following definitions apply to the terms as used throughout thisspecification, unless otherwise limited in specific instance.

Unless otherwise indicated, the term “lower alkyl”, “alkyl” or “alk” asemployed herein alone or in combined form, e.g., aralkyl or haloalkyl,includes both straight and branched chain hydrocarbons, preferablycontaining 1 to 12 carbons in the case of alkyl or alk, in the normalchain, and preferably 1 to 4 carbons in the case of lower alkyl.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, t-butyl, or isobutyl, pentyl, hexyl, isohexyl, heptyl,4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl,dodecyl, and the like. Each alkyl group may be optionally substitutedwith 1 to 4 substituents which may include, but are not limited to, oneor more of the following groups; alkyl, alkenyl, alkynyl, aryl,cycloalkyl, heterocyclo, hydroxyl, cyano, nitro, amino, monoalkylamino,dialkylamino, hydroxylamino, sulfonate, sulfamido, oxo, carboalkoxy,carboxamido, acyl, halo (e.g., a single halo substituent or multiplehalo substitutents forming, in the latter case, groups such as aperfluoroalkyl group or an alkyl group bearing C13 or CF3), alkoxy,alkylthio, carboxy (i.e., —COOH), alkoxycarbonyl, alkylcarbonyloxy,carbamoyl or substituted carbomoyl, carbamate, urea, amidinyl, thiol(i.e., —SH), —S-aryl, —S-heterocycle, —S(═O)-aryl, —S(═O)-heterocycle,arylalkyl-O—, —S(O)2-aryl, —S(O)2-heterocycle, —NHS(O)2-aryl,—NHS(O)2-heterocycle, —NHS(O)2NH-aryl, —NHS(O)2NH-heterocycle,—P(O)2-aryl, —P(O)2-heterocycle, —NHP(O)2-aryl, —NHP(O)2-heterocycle,—NHP(O)2NH-aryl, —NHP(O)2NH-heterocycle, —O-aryl, —O-heterocycle,—NH-aryl, —NH-heterocycle, —NHC(═O)-aryl, —NHC(═O)-alkyl,—NHC(═O)-heterocycle, —OC(═O)-aryl, —OC(═O)-heterocycle,—NHC(═O)NH-aryl, —NHC(═O)NH-heterocycle, —OC(═O)O-aryl,—OC(═O)O-heterocycle, —OC(═O)NH-aryl, —OC(═O)NH-heterocycle,—NHC(═O)O-aryl, —NHC(═O)O-heterocycle, —NHC(═O)O-alkyl, —C(═O)NH-aryl,—C(═O)NH-heterocycle, —C(═O)O-aryl, —C(═O)O-heterocycle,—N(alkyl)S(O)2-aryl, —N(alkyl)S(O)2-heterocycle, —N(alkyl)S(O)2NH-aryl,—N(alkyl)S(O)2NH-heterocycle, —N(alkyl)P(O)2-aryl,—N(alkyl)P(O)2-heterocycle, —N(alkyl)P(O)2NH-aryl,—N(alkyl)P(O)2NH-heterocycle, —N(alkyl)-aryl, —N(alkyl)-heterocycle,—N(alkyl)C(═O)-aryl, —N(alkyl)C(═O)-heterocycle, —N(alkyl)C(═O)NH-aryl,—N(alkyl)C(═O)NH-heterocycle, —OC(═O)N(alkyl)-aryl,—OC(═O)N(alkyl)-heterocycle, —N(alkyl)C(═O)O-aryl,—N(alkyl)C(═O)O-heterocycle, —C(═O)N(alkyl)-aryl,—C(═O)N(alkyl)-heterocycle, —NHS(O)2N(alkyl)-aryl,—NHS(O)2N(alkyl)-heterocycle, —NHP(O)2N(alkyl)-aryl,NHP(O)2N(alkyl)-heterocycle, —NHC(═O)N(alkyl)-aryl,—NHC(═O)N(alkyl)-heterocycle, —N(alkyl)S(O)2N(alkyl)-aryl,—N(alkyl)S(O)2N(alkyl)-heterocycle, —N(alkyl)P(O)2N(alkyl)-aryl,—N(alkyl)P(O)2N(alkyl)-heterocycle, —N(alkyl)C(═O)N(alkyl)-aryl, and—N(alkyl)C(═O)N(alkyl-heterocycle. In the aforementioned exemplarysubstitutents, in each instance, groups such as “alkyl”, “aryl” and“heterocycle” can themselves be optionally substituted; for example,“alkyl” in the group “NCH(═O)O-alkyl” recited above can be optionallysubstituted to that both “NHC(═O)O-alkyl” and “NHC(═O)O-substitutedalkyl” are exemplary substitutents.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or in combined form includes saturated cyclic hydrocarbon groupsor partially unsaturated (containing 1 or 2 double bonds) cyclichydrocarbon groups, containing at least one ring and a total of 3 to 7carbons, preferably 3 to 6 carbons, forming the ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, and the like.Cycloalkyl groups may optionally be substituted in the same manner asdescribed above for alkyl groups.

The term “aryl” as employed herein alone or in combined form, e.g.,aryloxy, refers to monocyclic and bicyclic aromatic groups containing 6to 10 carbons in the ring portion, such as phenyl, indenyl, indanyl, ornaphthyl including 1-naphthyl and 2-naphthyl and the like. Aryl groupsmay be optionally substituted through available carbon atoms with 1,2,or 3 groups selected from hydrogen, halo, alkyl, cycloalkyl, aralkyl,heterocyclo, haloalkyl, alkoxy, aryloxy, haloalkoxy, alkenyl,trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino, nitro,cyano, carbalkoxy, alkoxycarbonyl, alkylcarbonyloxy, acyl,hydroxylamine, sulfonate, sulfamide, cyano-guanidine, SO_(n) where n is0, 1, or 2, carboxamido groups, or monosubstituted amino, ordisubstituted amino, wherein the amino substituents are independentlyalkyl, aralkyl, aryl, acyl, or carbalkoxy groups.

The term “aralkyl” as used herein refers to an aryl group, as definedabove, bonded directly through an alkyl moiety, such as benzyl group,for example. An aralkyl group may be optionally substituted with anygroup described herein as an aryl or alkyl substitutent.

Unless otherwise indicated, the term “lower alkenyl” or “alkenyl” asused herein by itself or in combined form refers to straight or branchedchain radicals of 2 to 12 carbons, preferably 2 to 5 carbons, in thenormal chain, which include one to six double bonds in the normal chain,such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl,2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl,3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, and the like, which maybe optionally substituted in the same manner as that described for alkylgroups.

Unless otherwise indicated, the term “lower alkynyl” or “alkynyl” asused herein by itself or in combined form refers to straight or branchedchain radicals of 2 to 12 carbons, preferably 2 to 8 carbons, in thenormal chain; which include one triple bond in the normal chain, such as2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl,3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl,4-decynyl, 3-undecynyl, 4-dodecynyl and the like, which may optionallybe substituted in the same manner as that described for alkyl groups.

The normal carbon chain of any alkyl, alkenyl, alkynyl, or aralkyl groupmay optionally be interrupted by one or more heteroatoms.

As used herein, the term “acyl” refers to a group of the formula C(O)R,wherein R represents a hydrogen atom, an alkyl group, an aryl group, aheterocycle, or an aralkyl group.

As used herein, the term “carbalkoxy” refers to a group of the formulaC(O)OR, wherein R represents a hydrogen atom, an alkyl group, an arylgroup, a heterocycle, or an aralkyl group.

As used herein, the term “carboxamido” refers to a group of the formulaC(O)NR₂, wherein the R groups, which may be the same or different,represent a hydrogen atom, an alkyl group, an aryl group, a heterocycle,or an aralkyl group. Alternatively, the two R groups, when takentogether with the nitrogen atom, may form a heterocyclo group.

As used herein, “alkylamidinyl” refers to a nitrogen radical having thegeneral formula (NH₂)(alkyl)C═N—. The alkyl portion of an alkylamidinylgroup may optionally be substituted in the same manner as describedabove for alkyl groups.

The terms “heterocyclo”, “heterocyclic” and “heterocycle” as used hereinrefer to an optionally substituted, aromatic or non-aromatic cyclicgroup, which, for example, is a 4 to 7 membered monocyclic, 7 to 11membered bicyclic, or 10 to 15 membered tricyclic ring system, which hasat least one heteroatom in at least one carbon atom-containing ring.Each ring of the heterocyclic group containing a heteroatom may have 1,2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms andsulfur atoms, where the nitrogen and sulfur heteroatoms may alsooptionally be oxidized and the nitrogen heteroatoms may also optionallybe quaternized. The heterocyclic group may be attached at any heteroatomor carbon atom.

Examples of suitable monocyclic heterocyclic groups includepyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl,imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl,N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydrothiopyranyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, tetrahydrothiopyranylsulfone, thiamorpholinylsulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl,isothiazolidinyl, thietanyl, thiiranyl, triazinyl, triazolyl, and thelike.

Examples of suitable bicyclic hetrocyclic groups include indolyl,benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl,quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl] orfuro[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl, benzoxodiazol, benzothiodiazol, and the like.

In preferred embodiments, at least one of the heteroatoms in theheterocycle is a nitrogen atom.

Examples of suitable substituents for heterocyclic groups include one ormore alkyl groups as described above or one or more groups describedabove as alkyl or aryl substituents. Also suitable are aryl groups andsmaller heterocycles, such as epoxides and aziridines.

The term “heteroatom” as used herein includes oxygen, sulfur andnitrogen, where the nitrogen and sulfur heteroatoms may also optionallybe oxidized and the nitrogen heteroatoms may also optionally bequaternized.

The term “halogen” or “halo” as used herein alone or as part of anothergroup refers to fluorine, chlorine, bromine, and iodine.

As used herein, the expression “optionally substituted,” as in“optionally substituted lower alkyl”, “optionally substituted aryl” orthe like, refers to alkyl, aryl, and other groups which may beunsubstituted or substituted with the substituents mentioned above.Further, when a moiety is described herein as optionally substitutedwith more than one substituent, it is intended that each of the multiplesubstituents be chosen independently from among the substituentsmentioned above.

As used herein, the term “about” means that amounts, sizes,formulations, parameters, and other quantities and characteristics arenot and need not be exact, but may be approximate and/or larger orsmaller, as desired, reflecting tolerances, conversion factors, roundingoff, measurement error and the like, and other factors known to those ofskill in the art. In general, an amount, size, formulation, parameter orother quantity or characteristic is “about” or “approximate” whether ornot expressly stated to be such.

Compounds of the Invention

In accordance with the present invention, compounds having formula I,below, are provided.

In compounds of formula I, R₁ is selected from the group consisting ofH, hydroxyl, alkyl, amino, aralkyl, halogen, —R₁′, —C(O)R₁′, —C(O)OR₁′,—C(O)NR₁′R₁″, —S(O)₂R₁′″, —S(O)₂NR₁′R₁″, OR₁′, OC(O)R₁′, OC(O)OR₁′,OC(O)NR₁′R₁″, OS(O)₂R₁′″, and OS(O)₂NR₁′R₁″;

R₁′ and R₁″ are each independently selected from the group consisting ofH, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, aralkyl, amino,heterocyclo, cycloalkyl and alkylamidinyl groups; R₁′ and R₁″ may alsobe taken together to form one of a cycloalkyl, an aryl, and aheterocyclic group;

-   -   R₁′″ is selected from the group consisting of H, alkyl, aryl,        aralkyl, heterocyclo, and cycloalkyl;

R₂ is selected from the group consisting of H, alkyl, cycloalkyl, aryl,heterocycle, aralkyl, R₁′OC(O)—, R₁′C(O)NR₁′, R₁′C(O)—, R₁′C(S)—,R₁″R₁′NC(O)—, R₁′R₁″CN—, R₁′N═C—R₁′″O(O)₂S, R₁′R₁″N(O)₂S andR₁′″(O)_(n)S; wherein n is the integer 1 or 2;

R₁ and R₂ may be taken together to form a cycloalkyl, aryl, orheterocyclic group;

X is selected from the group consisting of a valence bond, —CH₂—, O,—CO, —C(O)₂, S, S(O)_(m) and NR₂′; wherein m is 0, 1 or 2; and R₂′ isselected from the group consisting of H, alkyl, aralkyl, C(O)R₁,C(O)OR₁, SO₂NR₁″, C(O)NR₁′R₁″ and SO₂R₁′″; with the proviso that when Xis S, R₂ is selected from the group consisting of H, alkyl, cycloalkyl,aryl, heterocycle and aralkyl;

R₃ is selected from the group consisting of H, hydroxyl, alkyl,cycloalkyl, heterocycle, aryl, aralkyl, acyl, carbalkoxy, carboxamido,halogen, amine, substituted amine, OR₃′, CH₂OR₃′, CH₂NR₃′R₃″, CH₂SR₃′,OC(O)R₃′, OC(O)OR₃″, OC(O)NR₃′R₃″, OS(O)₂R₃′, and OS(O)₂NR₃′R₃″; whereinR₃′ and R₃″ are each independently selected from the group consisting ofH, alkyl, aralkyl, heterocycle, cycloalkyl, and aryl; R₃′ and R₃″ mayalso be taken together to form a cycloalkyl, aryl, or heterocyclicgroup; when R₃ is a carbalkoxy, acyl, or carboxamido group, these groupsare optionally substituted with one or two substituent groups, saidsubstituent groups are independently selected from the group consistingof H, alkyl, aralkyl, heterocycle, cycloalkyl, and aryl; saidsubstituent groups may also be taken together to form a cycloalkyl,aryl, or heterocyclic group;

R₂ and R₃ may also be taken together to form a cycloalkyl, aryl, orheterocyclic group;

R₄ is selected from the group consisting of H, alkyl, cycloalkyl, aryl,heterocycle, aralkyl, R₁′OC(O), R₁′C(O), R₁″R₁′NC(O), R₁′″O(O)₂S,R₁′R₁″N(O)₂S and R₁′″(O)_(n)S, wherein n is the integer 1 or 2;

Y is selected from the group consisting of a valence bond, O, S,S(O)_(m) and NR₄′; wherein m is 0, 1 or 2; R₄′ is selected from thegroup consisting of H, alkyl, aralkyl, a heterocycle, C(O)R₁, C(O)OR₁,S(O₂)NR₁′R₁″, C(O)NR₁′R₁″, and S(O₂)R₁; with proviso that when Y is S,R₄ is selected from the group consisting of alkyl, cycloalkyl, aryl,heterocycle and aralkyl; when Y is NR₄′, R₄′ can be taken together withR₃ to form a heterocyclic ring system;

R₅ is selected from the group consisting of H, halogen, cyano, alkyl,cycloalkyl, a heterocycle, aryl, aralkyl, acyl, substituted alkylenegroup, R₁′OC(O), R₁′C(O), R₁″R₁′NC(O), R₁′″O(O)₂S, R₁′R₁″N(O)₂S andR₁′″(O)_(n)S; wherein n the integer 1 or 2;

Z is selected from the group consisting of a valence bond, O,—C(NR⁸)—NR⁹—NR¹⁰R¹¹, S, S(O)_(p) and NR₅′; wherein p is 0, 1 or 2; R₅′is selected from the group consisting of H, alkyl, aralkyl and aheterocycle; with the proviso that when Z is a valence bond, R₅ isselected from the group consisting of H, halogen, a substituted alkylenegroup and a cyano group; and, with the further proviso that when Z is S,R₅ is selected from the group consisting of H, alkyl, cycloalkyl, aryl,heterocycle and aralkyl;

R₆ is selected from the group consisting of H, alkyl, cycloalkyl, aryl,aralkyl, a heterocycle, acyl, carbalkoxy, and carboxamido; saidcarbalkoxy, acyl, and carboxamido groups are optionally substituted withone or two substituent groups, each of which is independently selectedfrom the group consisting of H, alkyl, aralkyl, and a heterocycle; and

R⁸, R⁹, R¹⁰, and R¹¹ are independently H, alkyl, or cycloalkyl.

Also included in the invention are the salts, solvates, andstereoisomers enantiomers, and diastereomers of the compounds of formulaI.

All stereoisomers of the compounds of formula I are contemplated, eitherin admixture or in pure or substantially pure form. A compound offormula I may have asymmetric centers at any of its non-aromatic carbonor nitrogen atoms, including those carbon atoms in any of itssubstituents. Consequently, compounds of formula I can exist inenaniomeric or diastereomeric forms or in mixtures thereof. Theprocesses for preparation can utilize racemates, enantiomers ordiastereomers as starting materials. When diastereomeric or enantiomericproducts are prepared, they may be separated by conventional methods,for example, chromatographic or fractional crystallization.

Preferred compounds of the invention are compounds of formula I whereinZ is a valence bond and R₅ is cyano.

In some preferred embodiments, R₃ is an alkyl, aryl or heteroaryl, andis preferably methyl.

In some preferred embodiments, Y is NR₄′. In still further embodiments,X is a valence bond, —CH₂—, O, or NR₂′, R₂′ is preferably R₁′C(O) or—C(O)NR₁′R₂′ or —C(O)OR₁′.

According to some embodiments of the present invention, R₁′ and R₂″ areindependently H, alkyl, cycloalkyl, or heterocycloalkyl.

Other preferred compounds are compounds of formula I wherein R₄ is anoptionally substituted phenoxyaniline. Also preferred are compounds offormula I wherein Y is NR₄′ wherein R₄′ is as defined above, or whereinY is O, and R₄ is an aryl or heteroaryl group.

Other preferred compounds of the invention are compounds of formula Iwherein Z is a valence bond, R₅ is cyano, and R₃ is methyl. Preferably,these compounds have one or more of the following substituents: Y isNR₄′; R₁′ and R₁″ are independently H, alkyl, cycloalkyl, orheterocycloalkyl; R₄ is alkyl, aryl or heteroaryl; X is a valence bond,O, NR₂′ or S(O)_(m), wherein m is 0, 1 or 2; and R₂ is R₁′C(O),—(C(O)NR₁′R₂′, or —C(O)OR₁′.

Additional preferred compounds of formula I include those in which Z isa valence bond, R₅ is cyano, Y is NR₄′ wherein R₄′ is as defined above,and R₄ is a phenyl group or heteroaryl group with one or moresubstitutions.

Further preferred compounds are illustrated in the examples below.

Methods of Making the Compounds

Generally, compounds of formula I may be made by reacting a pyrrole offormula II:

wherein X, R₁, R₂, and R₃ are as previously defined, with an aminatingagent in the presence of a base to produce the aminated pyrrole offormula III:

wherein X, R₁, R₂, and R₃ are as previously defined.

The compound of formula III is reacted with a carbonyl of formulaR₆C(O)CH₂ZR₅ or an acetal of the formula (RO)₂CR₆CH₂ZR₅, wherein R is analkyl group and Z, R₅, and R₆ are as previously defined, underring-closure conditions to produce a compound of formula IV.

4-Oxo-pyrrolopyridazines of formula IV may be reacted with a reagentproviding a leaving group, such as POCl₃ or POCl₅, to yield a compoundof formula V

wherein L is a leaving group.

The compound of formula V may be reacted with a compound of the formulaHYR₄, wherein Y and R₄ are as previously defined, to produce a compoundof formula I, above.

The compounds of formula I may be prepared by the processes described inthe following reaction schemes. Examples of suitable reagents andprocedures for conducting these reactions appear hereinafter and in theworking examples. Protection and deprotection in the schemes herein maybe carried out by procedures generally known in the art. (See, forexample, T. W. Greene & P. G. M. Wuts, Protecting Groups in OrganicSynthesis, 3rd Edition, Wiley, (1999)). In schemes A though D, unlessotherwise noted, X, Y, X, R₁, R₂, R₃, R₄, R₅, and R₆ are as definedabove. The variables L and L′ represent leaving groups. Variablesdesignated with the subscript “a” or “b” have the same scope as, but arechosen independently of, their parent variable. For example, R_(2a),R_(2a)′, and R_(2a)″ are coextensive with, but not necessarily identicalto, R₂, R₂′, and R₂″, respectively.

Pyrroles of formula II may be obtained by the processes described inPatent Cooperation Treaty (PCT) publication No. WO 00/71129, pendingU.S. patent application Ser. No. 09/573,829, pending PCT Application No.US01/49982 and pending U.S. patent application Ser. No. 10/036,293 (allof which are herein incorporated by reference in their entirety).

Treatment of a pyrrole of formula II with a base in a suitable reactionmedium followed by the addition of an aminating reagent generates anaminopyrrole of formula III. Suitable bases include sodium hydride(NaH), n-BuLi, t-BuLi, NaOH, lithium diisopropylamide (LDA), and lithiumhexamethyldisilazide (LiHMDS). Suitable reaction media includetetrahydrofuran (THF), CH₂Cl₂, dimethylformamide (DMF), CH₃CN andtoluene. Suitable aminating reagents include 2,4-dinitroaminophenol,NH₂OSO₃H and ClNH₂. Preferably the aminating reagent is ClNH₂ or2,4-dinitroaminophenol. Preferably, the base is NaH or LDA, the reactionmedium is DMF or THF. More preferably, the base is NaH, the reactionmedium is DMF, and the aminating reagent is 2,4-dinitroaminophenol.

Condensation of the compound of formula III with an acetal followed bybase induced cyclization in a suitable reaction medium provides apyrrolopyridazine of formula IV. Suitable bases include NaOH, LDA,diisopropylethylamine (DIPEA), 1,8-diazoicyclo[5,4,0]undec-7-ene (DBU),and K₂CO₃. Suitable reaction media include THF, CH₂Cl₂, DMF and toluene.Preferably, the base is DBU, DIPEA or LDA and the reaction medium istoluene or DMF. More preferably, the base is DBU or DIPEA, and thereaction medium is toluene. Alternatively, compounds of formula IV maybe obtained by the reactions of Schemes H, J and K, below.

Conversion of the oxo group at position 4 of the compound of formula IVto a leaving group L, as in compounds of formula V, can then beaccomplished using a suitable halogenating reagent, such as SOCl₂, POCl₃and POCl₅. More preferably, the reagent is POCl₃.

Treatment of a compound of formula V with a reagent of formula HY-R₄ inthe presence of a base in a reaction medium then provides compounds offormula VI, which are compounds of formula I wherein R₆ is H. Suitablebases include NaH, Et₃N, DIPEA, K₂CO₃ or Na₂CO₃ and suitable reactionmedia include THF, DMF, CH₂Cl₂ or CH₃CN. Preferably, the base is NaH,Et₃N or K₂CO₃ and the solvent is CH₃CN or DMF. More preferably, the baseis triethylamine and the reaction medium is acetonitrile.

Compounds of formula VIa, which are compounds of formula VI wherein X isa valence bond, R₂ represents CO₂R₂′, ZR₅ represents CN, and R₆represents hydrogen, may be saponified with a base to prepare carboxylicacids of formula VII as shown above in Scheme B. Suitable bases NaOH,KOH, LiOH, and Ba(OH)₂. Preferably, the base is an alkali metalhydroxide. More preferably, the base is NaOH.

Compounds of formula VIII, which are compounds of formula VI in whichR₂X is R_(2a)′R_(2a)″NC(O), ZR₅ represents CN, and R₆ representshydrogen, may be prepared via treatment of compounds of formula VII witha coupling reagent and an amine of formula NH₂R_(2a)′R_(2a)″ in areaction medium. Suitable coupling agents include PyBOP[benzotriazol-1-yloxytripyrrolidino-phosphonium hexafluorophosphate],BOP [benzotriazol-1-yloxytris(dimethylamino) phosphoniumhexafluorophosphate], CDI (N,N′-carbonyldiimidazole), DCC(N,N′-dicyclohexylcarbodiimide), HBTU[O-benzotriazol-1-yl-N,N,N′,N′-tetranethyluronium hexafluorophosphate],HOAt (1-hydroxy-7-azabenzotriazole) and HOBt (1-hydroxybenzotriazole)and EDC [1-ethyl-3-(3-dimethylaminopropyl) carbodimide]. Preferably, thecoupling reagent is HOBt, PyBOP or EDC. More preferably, the couplingreagent is HOBt or PyBOP.

Compounds of formula IX, which are compounds of formula VI wherein XR₂is R_(2a)′OC(O), ZR₅ represents CN, and R₆ represents hydrogen, may beprepared via treatment of a compound of formula VII with an acid or abase and an alcohol of the formula R_(2a)′OH. Suitable acids includeHCl, H₂SO₄, TsOH, 10-camphorsulfonic acid (CSA) and pyridiniump-toluenesulfonates (PPTs). More preferably, the acid is hydrochloricacid.

Compounds of formula X, which are compounds of formula VI where XR₂ isR_(2a)′OC(O)NR_(2a)″, ZR₅ represents CN, and R₆ represents hydrogen, maybe prepared via treatment of compounds of formula VII with anazidization reagent, that is, a source of N₃, followed by the additionof an alcohol of formula R_(2a)′OH. Suitable azidization reagentsinclude diphenylphosphorylazide (DPPA) and NaN₃. Preferably, the reagentis DPPA.

As shown in Scheme C, compounds of formula XII, which are compounds offormula I wherein XR₂ is NH(R_(2a)′)₂, may be prepared via compounds offormula X where the carbalkoxy moiety of the compound of formula Xfunctions as a removable protecting group. The intermediate compound offormula XI may be prepared by removal of the carbalkoxy moiety of thecompound of formula X. Preferably, the carbalkoxy group will be at-butoxycarbonyl (BOC) or benzyloxycarbonyl (Cbz or Z). Suitableconditions for removing these and other suitable protecting groups aredisclosed in Green and Wuts, supra. Preferably, the deprotectionreaction is an acid cleavage or a hydrogenation reaction.

Compounds of formula XII result from the reductive amination ofcompounds of formula XI using an aldehyde of formula R_(2a)′CHO and areducing agent in a suitable reaction medium. Suitable reducing agentsinclude NaBH₄, LiBH₄, diisobutylaluminum hydride (DIBAL-H), lithiumaluminum hydride (LAH) and NaBH(OAc)₃. Preferably, the reducing agent isNaBH(OAc)₃ or NaBH₄. More preferably, the reducing agent is NaBH(OAc)₃.Suitable reaction media include 1,2-dichloroethane, CH₂Cl₂, THF andCH₃CN. Preferred reaction media include 1,2-dichloroethane and CH₂Cl₂and more preferably, the reduction is carried out in 1,2-dichloroethane.

Alternatively, preparation of compounds of formula XII may beaccomplished via treatment of compounds of formula XI with a base and arequest of formula R_(2a)′L. Suitable bases include K₂CO₃, NaHCO₃, Et₃N,DIPEA, Cs₂CO₃, DBU and pyridine. Preferably, the base is selected fromthe group consisting of K₂CO₃, NaHCO₃ and Et₃N. More preferably, thebase is sodium bicarbonate.

Compounds of formula XV may be prepared via the method shown in SchemeD. Net reduction of compounds of formula VI wherein XR₂ is R₂′OC(O)provides aldehydes of formula XIII. Suitable means of carrying out a netreduction include reaction with a reducing agent or sequential reactionwith a stronger reducing agent and a weaker oxidizing agent. Suitablereducing agents are generally known to those skilled in the art and canbe fuond in references such as Advanced Organic Chemistry III ed., PartB: Reactions and Synthesis, Francis A. Carey, Richard J. Sundberg,Plenum Publishing Corp., NY (1993) and March's Advanced OrganicChemistry: Reactions, Mechanisms and Structure, 5^(th) ed.,Wiley-InterScience, John Wiley & Sons, Inc., NY (2001) (both hereinincorporated by reference).

Suitable combinations of oxidizing agents and reducing agents includediisobutylaluminum hydride (DIBAL-H) with MnO₂. Preferably, netreduction is accomplished by sequential reduction and oxidation with areducing agent such as DIBAL-H, LAH, NaBH₄ or LiBH₄, and an oxidizingagent such as MnO₂, SO₃-pyridine, TEMPO(2,2,6,6-tetramethyl-1-piperidinyloxy, free radical), Dess-Martinperiodinane, or TPAP (tetrapropylammonium perruthenate) and NMO(N-methylmorpholine-N-oxide) in combination. More preferably, thereduction is carried out first with DIBAL-H to produce an intermediatecompound, which is then oxidized with MnO₂ to yield the compound offormula XIII.

Subsequent treatment with an oxidizing agent in a suitable reactionmedium followed by etherification using a base in a suitable reactionmedium and a reagent of formula R_(2a)′L yields compounds of formula XV,which are compounds of formula VI wherein XR₂ is OR_(2a)′. Suitableoxidizing agents include m-chloroperbenzoic acid (m-CPBA) and H₂O₂.Suitable bases include NaH, Et₃N, DIPEA and K₂CO₃. Suitable reactionmedia include THF, DMF, CH₂Cl₂ and CH₃CN. More preferably, the oxidizingagent is m-chloro perbenzoic acid (m-CPBA), the base is NaH, and thereaction medium is tetrahydrofuran (THF) or DMF.

Halogenation of the 5-methyl group of a compound of formula V may beeffected by treatment with a halogenating agent. Suitable halogenatingagents include, but are not limited to sulfuryl choride,N-Iodosuccinimide, N-Bromosuccinimide, N-chlorosuccinimide, oxalylchoride. Preferably the halogenating agent is N-bromosuccinimide orsulfuryl chloride. The halogenation can be performed under an inertatmosphere, such as N₂, in the presence of a catalyst, to produce ahalogenated pyrrole intermediate of formula XVI. Preferably, thecatalyst is dibenzoyl peroxide or 2,2′-azobisisobutyronitrile, orirradiation.

Treatment of pyrrole of formula XVI with a thiol of formula HSR_(3a)′,an alcohol intermediate of formula HOR_(3a)′, or a primary or asecondary amine of formula HNR_(3a)′R_(3a)″ in the presence of a baseaffords a pyrrole of formula XVII. Suitable bases include NaHCO₃,diisopropyle ethylamine DBU, KHCO₂, and trimethylamine. Preferably, thebase is NaHCO₃ or triethylamine. Acetonitrile is one suitable reactionmedium for this reaction.

Treatment of a pyrrole of formula XVII with a reagent of formula HYR₄,at room temperature in the presence of a base yields the compound offormula XVIII. Preferably, the base is NaHCO₃ or triethylamine.Acetonitrile is one suitable reaction medium for this reaction. Heatingthe pyrrole of formula XVII with a reagent of formula HYR₄ in theabsence of base also affords the compound of formula XVIII.

Compound XIX, which is a compound of formula VI wherein R₃ is—CH₂SR_(3a)′ (see Scheme A, above), can be oxidized to the sulfoxide ofcompound XX, wherein n=1, or the sulfone of compound XX, wherein n=2.Suitable oxidizing agents include m-chloroperbenzoic acid (MCPDA),tBu-OOH, H₂O₂ NaIO₄, and dimethyldioxirane. Preferably, the oxidizingagent is MCPDA. The number of equivalents of oxidizing agent added tothe reaction mixture will determine the final oxidation state of thesulfur atom. A compound of formula XX wherein n=1 or 2 can be heatedwith an excess of an alcohol of formula HOR_(3b)′ or a primary orsecondary amine of formula HNR_(3b)′R_(3b)″ to yield a compound offormula XXI.

Compounds of formula VII, from Scheme B, undergo a Wittig reaction witha phosphonate in the presence of a base to afford a compound of formulaXXII. Suitable phosphonates known to those skilled in the art may beused. Preferably, the phosphonate is methyl diethylphosphonoacetate.Dichloroethane and the like are suitable organic reaction media forWittig reactions. Suitable bases include KH, K₂CO₃, N-Butyllithium,sec-Butyllithium, tert-Butyllithium, NaH, preferably NaH.

The double bond in the R₂ group of the compound of formula XXII may behydrogenated in the presence of a catalyst to yield a compound offormula XXIII. Suitable catalysts include PtO₂, palladium on carbon(Pd/C), Pd(OH)₂, and Raney Ni. Preferably, the catalyst is Pd/C.

Esters of formula XXIII may be hydrolyzed by techniques well known inthe art, for example those taught in Green and Wuts, supra, preferablybase hydrolysis with NaOH. Subsequent coupling of the resulting acidwith an amine in the presence of a coupling agent affords the amide offormula XXIV. Suitable coupling agents are known to those skilled in theart and include those described in The Practice of Peptide Synthesis,2^(nd) Ed., by Bodanszy, Miklos, Springer-Velag (1993) (hereinincorporated by reference). Preferably the coupling agent isN,N′-dicyclohexylcarbodiimide (DCC).

Scheme H depicts an alternative route to the synthesis of compounds offormula IV (see Scheme A, above). Condensation of a pyrrole of formulaIII with a reagent of formula R₆C(O)CH₂ZR₅, followed by base inducedcyclization in a suitable reaction medium, yields the intermediate offormula IV. Suitable bases include DBU, NaH, BuLi, Et₃N and DIPEA.Suitable reaction media include toluene, THF, CH₂Cl₂, DMF, toulene andCH₃CN. Preferably the base is NaH, DBU, or DIPEA and the reaction mediumis DMF, toluene or THF. Reagents of formula R₆C(O)CH₂ZR₅, particularlythose wherein R₆ is a substituted oxygen, nitrogen or an alkyl group andZR₅ is a nitrile group, can be purchased from commercial sources or elsereadily synthesized by those of skill in the art.

As shown in scheme I, a compound of formula XXV, which is a compound offormula VI wherein ZR₅ is a nitrile group (see Scheme A, above), can bereduced in the presence of hydrogen and a catalyst to yield a compoundof formula XXVI. Suitable catalysts include PtO₂, Pd/C, Pd(OH)₂, andRaney Ni. Preferably, the catalyst is palladium on carbon (Pd/C).

Compounds of formula XXVI, when combined with a reagent of formulaR_(5a)L, wherein L is a leaving group, e.g., a halogen, in the presenceof a base, yield compounds of formula XXVII. Suitable bases KH, K₂CO₃,N-Butyllithium, sec-Butyllithium, tert-Butyllithium, and NaH.Preferably, the base is NaH. Reagents of formula R_(5a)L are readilyavailable from commercial sources.

Additionally, a compound of formula XXVI can be treated with a reagentof formula (R_(5b)—Z_(b)—C(O))₂O or R_(5b)—Z_(b)—C(O)-L′, wherein L′ isa leaving group, e.g., a halogen, in the presence of a base to yield acompound of formula XXVII. Suitable bases include NaHCO₃,diisopropylethylamine, DBU, KHCO₃, trimethylamine. Preferably, the baseis triethylamine. Reagents of formula R_(5b)—Z_(b)—C(O)—L′ or(R_(5b)—Z_(b)—C(O))₂O are readily available from commercial sources, ormay be synthesized by those of skill in the art.

Scheme J depicts the synthesis of a compound of formula XXX, which is acompound of formula IV (see scheme A, above) wherein R₆ is hydrogen andZR₅ is a nitrile group. Treatment of a pyrrole of formula III with areactive intermediate in a high boiling protic solvent yields anintermediate of formula XXIX. Preferably, dimethylformamide (DMF) anddimethylacetamide are used.

Treatment of the intermediate of formula XXIX with acetonitrile in thepresence of a base results in cyclization to produce the compound offormula XXX. Suitable bases include, but are not limited to KH, NaH,sec-butyllithium, and preferably N-Butyllithium. As shown in scheme A,above, compounds of formula XXX are intermediates in the synthesis ofcompounds of formula I wherein R₆ is hydrogen and ZR₅ is a nitrilegroup.

The synthesis of compounds of formula XXXIV and XXXV is shown in SchemeK. Compounds of formula XXXIV and XXXV are intermediates of formula IV(see scheme A, above) wherein R₆ is hydrogen and ZR₅ is a nitrile group.Treatment of a pyrrole of formula XXXI with a reactive intermediate offormula XXXII in a high boiling solvent yields an intermediate offormula XXXIII. Suitable solvents include but are not limited to xylene,nitrobenzene and toluene, preferably toluene.

Further heating of an intermediate of formula XXXIII in a high boilingsolvent results in cyclization to yield intermediates of formula XXXIVand XXXV. Suitable solvents include but are not limited to DMF, DMA,N-methylpyrolidinone, preferably Dowtherm™, or toluene in a highpressure apparatus.

The synthesis of compounds of formula XXXVI is shown in Scheme L.Treatment a compound of formula XXI, from Scheme F, with a reactiveintermediate of formula X′C(O)X′ or X′C(O)OC(O)X′, as decribed in SchemeL, in presence of a base such as diisopropylethyl amine or triethylamine, with or without heating, yields a compound of formula XXXVI.Suitable solvents include, but are not limited to, methylene chloride,chloroform, tetrahydrofurane or ethyl acetate.

As shown in scheme K, above, compounds of formula XXXIV and XXXV areintermediates in the synthesis of compounds of formula I wherein R₆ ishydrogen and ZR₅ is a nitrile group. The reactive intermediate offormula XXXII and related reagents of this structure are readilyavailable from commercial sources, or may be synthesized by those ofskill in the art.

Schemes 1 through 5, below, summarize several preferred methods ofmaking some of the compounds of the invention. In schemes 1 through 5,unless otherwise noted, X, Y, Z, R₁, R₂, R₂′, R₃, R₄, R₅ and R₆ are asdefined above, and L represents a leaving group. Variables designatedwith the subscript “a” or “b” have the same scope as, but are chosenindependently of, their parent variable.

3-Cyanopyrrolopyridazines of formula VI may be prepared in accordancewith Scheme 1. Pyrroles of formula II may be obtained by the processesdescribed in Patent Cooperation Treaty (PCT) publication No. WO00/71129, pending U.S. patent application Ser. No. 09/573,829, pendingPCT Application No. US01/49982 and pending U.S. patent application Ser.No. 10/036,293 (all of which are herein incorporated by reference intheir entirety).

Treatment of a pyrrole of formula II with a base such as sodium hydridein a reaction medium such as DMF followed by the addition of anaminating reagent such as 2,4-dinitroaminophenol generates anaminopyrrole of formula III. Condensation with an acetal such as1,1-diethoxypropionitrile followed by base induced cyclization employinga base such as DBU or diisopropylethylamine, in a reaction medium suchas toluene, provides the 3-cyanopyrrolopyridazine of formula IV.Conversion to the 4-chloro compounds of formula V can then beaccomplished using a chlorinating reagent such as POCl₃ or POCl₅.Treatment of a compound of formula V with a reagent of formula HY-R₄ inthe presence of a base such as triethylamine in a reaction medium suchas acetonitrile provides compounds of formula VI, which are compounds offormula I wherein XR₂ is C(O)OEt, Z is a valence bond, R₅ is CN, and R₆is H.

Compounds of formula VI may be saponified with a base such as NaOH toprepare carboxylic acids of formula VII as shown above in Scheme 2.Compounds of formula VIII, which are compounds of formula I wherein XR₂is C(O)NHR₂′, Z is a valence bond, R₅ is CN, and R₆ is H, may beprepared via treatment of compounds of formula VII with a couplingreagent such as EDC and an amine such as NHR_(2a)′R₂a″, in a reactionmedium such as dichloromethane. Compounds of formula IX, which arecompounds of formula I wherein XR₂ is C(O)OR₂′, Z is a valence bond, R₅is CN, and R₆ is H, may be prepared via treatment of compound VII withan acid such as hydrochloric acid and an alcohol of formula R₂′OH.Compounds of formula X, which are compounds of formula I where XR₂ isNHC(O)OR₂′, Z is a valence bond, R₅ is CN, and R₆ is H, may be preparedvia treatment of compounds of formula VII with a reagent such as DPPAfollowed by the addition of an alcohol of the formula R₂′OH.

As shown in Scheme 3, compounds of formula XII, which are compounds offormula I wherein XR₂ is NHR_(2a)′, Z is a valence bond, R₅ is CN, andR₆ is H, may be prepared from compounds of formula X where thecarbalkoxy of the compound of formula X is a removable protecting group(e.g., R₂′ is t-butyl or benzyl). The compound of formula XI may beprepared by deprotection, i.e., acid cleavage or hydrogenation,respectively. Compounds of formula XII may then be prepared viareductive amination of compounds of formula XI using an aldehyde offormula R_(2a)′CHO and a reducing agent such as NaBH(OAc)₃ in a reactionmedium such as 1,2-dichloroethane. Alternatively, preparation ofcompounds of formula XII may be accomplished via treatment of compoundsof formula XI with a base such as NaHCO₃ and a reagent of formulaR_(2a)′L.

Compounds of formula XV may be prepared via the method shown in Scheme4. Reduction of compounds of formula VI with a reducing agent such asDIBAL-H in reaction media such as dichloromethane or toluene, followedby oxidation with an oxidizing agent such as MnO₂, provides aldehydes offormula XIII. Treatment of compounds of formula XIII with a peracid suchas m-CPBA in a reaction medium such as dichloromethane followed byetherification using a base such as sodium hydride in reaction mediumssuch as tetrahydrofuran or DMF and a reagent of formula R_(2a)′L yieldscompounds of formula XV, which are compounds of formula I where XR₂ isOR_(2a)′, Z is a valence bond, R₅ is CN, and R₆ is H.

As shown in Scheme 5, an intermediate of formula XXV, which is acompound of formula I wherein R₆ is H and ZR₅ is a nitrile group, can bereduced in the presence of hydrogen, trifluoroacetic acid (TFA), and acatalyst such as Pd/C to yield an compound of formula XXVI. The compoundof formula XXVI can be treated with intermediates of formulaR_(5b)—Z_(b)—C(O)—Cl or (R_(5b)—Z_(b)—C(O))₂O in the presence of a basesuch as triethylamine to yield the compound of formula XXVII.Intermediates of formula R_(5b)—Z_(b)—C(O)—Cl and (R_(5b)—Z_(b)—C(O))₂)are readily available from commercial sources, or may be synthesized bythose of skill in the art.

Solvates (e.g., hydrates) of the compounds of formula I are also withinthe scope of the present invention. Methods of solvation are generallyknown in the art. Accordingly, the compounds of the instant inventionmay be in the free or solvated form.

The compounds of formula I may be present as salts, in particularpharmaceutically acceptable salts. Compounds of formula I having, forexample, at least one basic center can form acid addition salts. Theseare formed, for example, with strong inorganic acids, such as mineralacids, for example sulfuric acid, phosphoric acid or a hydrohalic acid,with strong organic carboxylic acids, such as alkanecarboxylic acids of1 to 4 carbon atoms which are unsubstituted or substituted, for example,by halogen, for example acetic acid, such as saturated or unsaturateddicarboxylic acids, for example oxalic, malonic, succinic, maleic,fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids,for example ascorbic, glycolic, lactic, malic, tartaric or citric acid,such as amino acids, (for example aspartic or glutamic acid or lysine orarginine), or benzoic acid, or with organic sulfonic acids, such as(C₁-C₄) alkyl or arylsulfonic acids which are unsubstituted orsubstituted, for example by halogen, for example methanesulfonic acid orp-toluenesulfonic acid. Corresponding acid addition salts can also beformed having, if desired, an additional basic center.

The compounds of formula I having at least one acid group (for exampleCOOH) can also form salts with bases. Suitable salts with bases are, forexample, metal salts, such as alkali metal or alkaline earth metalsalts, for example sodium, potassium or magnesium salts, or salts withammonia or an organic amine, such as morpholine thiomorpholine,piperidine, pyrrolidine, a mono-, di-, or tri-lower alkylamine, forexample ethyl, t-butyl, diethyl, diisopropyl, triethyl, tributyl ordimethyl-propylamine, or a mono, di, or trihydroxy lower alkylamine, forexample mono, di or triethanolamine.

Corresponding internal salts may furthermore be formed. Salts which areunsuitable for pharmaceutical uses but which can be employed, forexample, for he isolation or purification of free compounds of formula Ior their pharmaceutically acceptable salts, are also included within thescope of this invention.

Preferred salts of the compounds of formula I which include a basicgroup include monohydrochloride, hydrogen sulfate, methanesulfonate,phosphate or nitrate.

Preferred salts of the compounds of formula I which include an acidgroup include sodium, potassium and magnesium salts and pharmaceuticallyacceptable organic amines.

Methods of Using the Compounds

It has been discovered that pyrrolopyridazines of the invention areinhibitors of protein kinases. More specifically, certainpyrrolopyridazines inhibit the effects of receptor tyrosine kinases andserine/threonine kinases, a property of value in the treatment ofdisease states associated with hyperproliferation, angiogenesis,increased vascular permeability, and inflammation, such as cancer andinflammatory disease. In particular, the compounds of formula I andtheir salts, solvates, and stereoisomers are expected to inhibit thegrowth of primary and recurrent solid tumors by antiproliferative and/orantiangiogenic mechanisms. The solid tumors include, for example,cancers of the bladder, squamous cell, head, colorectal, oesophageal,gynecologocal (such as ovarian), pancreas, breast, prostate, lung,vulva, skin, brain, genitourinary tract, lymphatic system (such asthyroid), stomach, larynx and lung

In some embodiments of the present invention, methods are provided fortreating proliferative or inflammatory diseases comprising administeringto a patient in need thereof a therapeutically effective amount of acompound having formula I, as described above.

The methods optionally comprise administering at least one othertherapeutic agent such as angiogenesis inhibitors, antiestrogens,progestogens, aromatase inhibitors, antihormones, antiprogestogens,antiandrogens, LHRH agonists and antagonists, testoterone5α-dihydroreductase inhibitors, farnesyl transferase inhibitors,anti-invasion agents, growth factor inhibitors, antimetabolites,intercalating antitumour antibiotics, platinum derivatives, alkylatingagents, antimitotic agents, topoisomerase inhibitors, cell cycleinhibitors, and biological response modifiers, linomide, integrin αvβ3function inhibitors, angiostatin, razoxin, tamoxifen, toremifen,raloxifene, droloxifene, iodoxyfene, megestrol acetate, anastrozole,letrazole, borazole, exemestane, flutamide, nilutamide, bicalutamide,cyproterone acetate, gosereline acetate, luprolide, finasteride,metalloproteinase inhibitors, urokinase plasminogen activator receptorfunction inhibitors, growth factor antibodies, growth factor receptorantibodies, tyrosine kinase inhibitors, serine/threonine kinaseinhibitors, methotrexate, 5-fluorouracil, purine, adenosine analogues,cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin,mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, nitrogenmustard, melphalan, chlorambucil, busulphan, cyclophosphamide,ifosfamide nitrosoureas, thiotephan, vincristine, taxol, taxotere,epothilone analogs, discodermolide anlogs, eleutherobin analogs,etoposide, teniposide, amsacrine, topotecan, flavopyridols, andbiological response modifiers. In some preferred embodiments, theadditional thereapeutic agent is selected from Erbitux™, taxol,paraplatin and Ifex.

More generally, the compounds of formula I are useful in the treatmentof a variety of cancers, including, but not limited to, the following:

-   -   carcinoma, including that of the bladder, breast, colon, kidney,        liver, lung, including small cell lung cancer, esophagus, gall        bladder, ovary, pancreas, stomach, cervix, thyroid, prostate,        and skin, including squamous cell carcinoma;    -   hematopoietic tumors of lymphoid lineage, including leukemia,        acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell        lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins        lymphoma, hairy cell lymphoma and Burkett's lymphoma;    -   hematopoietic tumors of myeloid lineage, including acute and        chronic myelogenous leukemias, myelodysplastic syndrome and        promyelocytic leukemia;    -   tumors of mesenchymal origin, including fibrosarcoma and        rhabdomyosarcoma;    -   tumors of the central and peripheral nervous system, including        astrocytoma, neuroblastoma, glioma and schwannomas; and    -   other tumors, including melanoma, seminoma, teratocarcinoma,        osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid        follicular cancer and Kaposi's sarcoma.

The compounds of formula I are especially useful in treatment of tumorshaving a high incidence of protein kinase activity, such as colon, lung,prostate, breast and pancreatic tumors. By the administration of acomposition comprising a compound of the invention, or a combination ofsuch compounds, development of tumors in a mammalian host is reduced.

Compounds of formula I may also be useful in the treatment of diseasesother than cancer that may be associated with signal transductionpathways operating through growth factor receptors. For example, due tothe key role of kinases in the regulation of cellular proliferation ingeneral, kinase inhibitors could act as reversible cytostatic agentswhich may be useful in the treatment of any disease process whichfeatures abnormal cellular proliferation, e.g., benign prostatehyperplasia, familial adenomatosis polyposis, neuro-fibromatosis,atherosclerosis, pulmonary fibrosis, arthritis, psoriasis,glomerulonephritis, restenosis following angioplasty or vascularsurgery, hypertrophic scar formation, inflammatory bowel disease,transplantation rejection, endotoxic shock, and fungal infections.

In addition, compounds of formula I may induce or inhibit apoptosis. Theapoptotic response is aberrant in a variety of human diseases. Compoundsof formula I, as modulators of apoptosis, will be useful in thetreatment of cancer (including but not limited to those types mentionedhereinabove), viral infections (including but not limited to herpevirus,poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), preventionof AIDS development in HIV-infected individuals, autoimmune diseases(including but not limited to systemic lupus erythematosus, autoimmunemediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, and autoimmune diabetes mellitus),neurodegenerative disorders (including but not limited to Alzheimer'sdisease, AIDS-related dementia, Parkinson's disease, amyotrophic lateralsclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellardegeneration), myelodysplastic syndromes, aplastic anemia, ischemicinjury associated with myocardial infarctions, stroke and reperfusioninjury, arrhythmia, atherosclerosis, toxin-induced or alcohol relatedliver diseases, hematological diseases (including but not limited tochronic anemia and aplastic anemia), degenerative diseases of themusculoskeletal system (including but not limited to osteoporosis andarthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiplesclerosis, kidney diseases and cancer pain.

As inhibitors of protein kinases, compounds of the present inventionhave utility in treating conditions associated with inappropriate kinaseactivity. Such conditions also include diseases in which cytokine levelsare modulated as a consequence of intracellular signaling, and inparticular, diseases that are associated with an overproduction of suchcytokines as IL-1, IL-4, IL-8 and TNF-α. For example, compounds of thepresent invention are useful in treating and preventing:

-   -   IL-1 mediated diseases such as, for example, rheumatoid        arthritis, osteoarthritis, stroke, endotoxemia and/or toxic        shock syndrome, inflammatory reaction induced by endotoxin,        inflammatory bowel disease, tuberculosis, antherosclerosis,        muscle degeneration, cachexia, psoriatic arthritis, Reiter's        syndrome, gout, traumatic arthritis, rubella arthritis, acute        synovitis, diabetes, pancreatic β-cell disease and Alzheimer's        disease;    -   IL-4 mediated diseases or conditions such as, for example,        allergic inflammatory processes including those that occur in        asthma,    -   IL-8 mediated diseases or conditions such as, for example, those        characterized by massive neutrophil infiltration, such as        psoriasis, inflammatory bowel disease, asthma, cardiac and renal        reperfusion injury, adult respiratory distress syndrome,        thrombosis and glomerulonephritis; and    -   TNF-mediated diseases or conditions such as rheumatoid        arthritis, rheumatoid spondylitis, osteoarthritis, gouty        arthritis and other arthritic conditions, sepsis, septic shock        syndrome, adult respiratory distress syndrome, cerebral malaria,        chronic pulmonary inflammatory disease, silicosis, pulmonary        sarcoisosis, bone resorption disease, reperfusion injury, graft        vs. host reaction, allograft rejections, fever and myalgias due        to infection, cachexia secondary to infection, AIDS, ARC or        malignancy, meloid formation, scar tissue formation, Crohn's        disease, ulcerative colitis, pyresis, viral infections, such as        HIV, CMV, influenza and herpes; and veterinary viral infections,        such as lentivirus infections, including, but not limited to        equine infectious anemia virus; or retrovirus infections,        including feline immunodeficiency virus, bovine immunodeficiency        virus, or canine immunodeficiency virus.

Diseases mediated by p38 include rheumatoid arthritis (RA), chronicobstructive pulmonary disease (COPD), asthma, Crohn's disease,meurological diseases such as Alzheimer's disease and stroke, andinflammatory bone diseases. A further discussion of diseases mediated byp38 can be found in pending PCT Application No. US01/49982 and pendingU.S. patent application Ser. No. 10/036,293 (both of which are hereinincorporated by reference in their entirety).

Inhibitors of protein kinase activity, such as the compounds of thepresent invention, are useful in treating and preventing otherconditions and classes of conditions including, but not limited to,inflammatory diseases, autoimmune diseases, destructive bone disorders,proliferative disorders, angiogenic disorders, infectious diseases,neurodegenerative diseases, viral diseases, allergies, myocardialischemia, reperfusion/ischemia in stroke heart attacks, organ hyposia,vascular hyperplasia, cardiac hypertrophy, thrombin-induced plateletaggregation, and conditions associated with prostaglandin endoperoxidasesynthase-2.

Inflammatory diseases which may be treated or prevented include, but arenot limited to, acute pancreatitis, chronic pancreatitis, asthma,allergies and adult respiratory distress syndrome.

Autoimmune diseases which may be treated or prevented include, but arenot limited to, glomerulonephritis, rheumatoid arthritis, systemic lupuserythematosis, scleroderma, chronic thyroiditis, Grave's disease,autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmuneneutropenia, thrombocytopenia, atopic dermatitis, chronic activehepatitis, myasthenia gravis, multiple sclerosis, inflammatory boweldisease, ulcerative colitis, Crohn's disease, psoriasis, or graft vs.host diseases.

Destructive bone disorders which may be treated or prevented include,but are not limited to, osteoporosis, osteoarthritis and multiplemyeloma-related bone disorder.

Proliferative diseases which may be treated or prevented include, butare not limited to, acute myelogenous leukemia, chronic myelogeneousleukemia, metastatic melanoma, Kaposi's sarcoma, and multiple myeloma.

Angiogenic disorders which may be treated or prevented includehemangiomas, psoriasis, Kaposi's sarcoma, ocular neovascularization,retinopathy of prematurity, macular degeneration, diabetic retinopathy,diabetic nephropathy, rheumatoid arthritis, endometriosis,atherosclerosis, tumor growth and metastasis, myocardial ischemia,peripheral ischemia, cerebral ischemia, impaired wound healing, certainfemale reproductive disorders, organ hypoxia, and impaired ulcerhealing.

Infectious diseases which may be treated or prevented include, but arenot limited to, sepsis, septic shock, and Shigellosis.

Neurodegenerative diseases which may be treated or prevented by thecompounds of this invention include, but are not limited to, Alzheimer'sdisease, Parkinson's disease, cerebral ischemias or neurodegenerativedisease caused by traumatic injury.

Viral diseases which may be treated or prevented include but are notlimited to, acute hepatitis infection (including hepatitis A, hepatitisB and hepatitis C), HIV infection and CMV retinitis.

The compounds of formula I may also prevent blastocyte implantation,and, therefore, may be used as contraceptives in mammals.

In addition, protein kinase inhibitors of this invention also exhibitinhibition of the expression of inducible pro-inflammatory proteins suchas prostaglandin endoperoxide synthase-2 (PGHS-2), also referred to ascyclooxygenase-2 (COX-2). Accordingly, additional conditions which maybe treated or prevented by appropriate administration of compounds ofthe invention include edemia, analgesia, fever and pain, such asneuromuscular pain, headache, pain caused by cancer, dental pain andarthritis pain.

In the field of medical oncology, it is normal practice to combinedifferent agents for treatment of patients with cancer. Thus, a compoundof formula I may optionally be combined with other components, such asantiproliferative, antiangiogenic and/or vascular permeability reducingagents. Additionally, surgery, radiotherapy or chemotherapy mayoptionally be utilized in conjunction with administration of compoundsof formula I. Accordingly, the compound of formula I may be administeredalone or combined with the administration of one or more othertherapeutic agents, substances and/or treatments.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate administration of the individual components ofthe treatment. When not administered simultaneously, the componenttherapies may be administered in any order. If formulated as a fixeddose, such combination products employ the compounds of this inventionwithin the dosage range described below and the other pharmaceuticallyactive agent within its approved dosage range. Dosage ranges of manypharmaceutically active agents may be found in the Physician's DeskReference, 55^(th) Edition, Medical Economics Company (2001). Compoundsof formula I may also be used sequentially with known anticancer orcytotoxic agents and treatment, including radiation, when a combinationformulation is appropriate.

In general, there are three main categories of chemotherapeutic agents:

-   -   (i) antiangiogenic agents, for example, linomide, inhibitors of        integrin αvβ3 function, angiostatin, and razoxin;    -   (ii) cytostatic agents such as antiestrogens (for example        tamoxifen, toremifen, raloxifene, droloxifene, iodoxyfene),        progestogens (for example megestrol acetate), aromatase        inhibitors (for example anastrozole, letrazole, borazole,        exemestane), antihormones, antiprogestogens, antiandrogens (for        example, flutamide; nilutamide; bicalutamide; cyproterone        acetate;        (R)-2,3,4,5-tetrahydro-1-(1H-imidazole-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile,        mesylate salt;        N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide,        hemi L-Tartaric acid salt; cetuximab; molecules disclosed in        pending U.S. patent application Ser. No. 10/025,116 (herein        incorporated by reference), LHRH agonists and antagonists (for        example gosereline acetate, luprolide), inhibitors of        testosterone 5α-dihydroreductase (for example finasteride),        farnesyl transferase inhibitors, anti-invasion agents (for        example metalloproteinase inhibitors like marimastat and        inhibitors of urokinase plasminogen activator receptor function)        and inhibitors of growth factor function, (such growth factors        include for example EGF, FGF, platelet derived growth factor and        hepatocyte growth factor such inhibitors include growth factor        antibodies, growth factor receptor antibodies, tyrosine kinase        inhibitors and serine/threonine kinase inhibitors); and    -   (iii) antiproliferative/antineoplastic drugs and combinations        thereof, as used in medical oncology, such as antimetabolites        (for example antifolates like methotrexate, fluoropyrimidines        like 5-fluorouracil, purine and adenosine analogues, cytosine        arabinoside); intercalating antitumour antibiotics (for example        anthracyclines like doxorubicin, daunomycin, epirubicin and        idarubicin, mitomycin-C, dactinomycin, mithramycin); platinum        derivatives (for example cisplatin, carboplatin); alkylating        agents (for example nitrogen mustard, melphalan, chlorambucil,        busulphan, cyclophosphamide, ifosfamide nitrosoureas,        thiotephan); antimitotic agents (for example vinca alkaloids        like vincristine and taxoids like taxol, taxotere and newer        microbtubule agents such as epothilone analogs, discodermolide        analogs, and eleutherobin analogs); topoisomerase inhibitors        (for example epipodophyllotoxins like etoposide and teniposide,        amsacrine, topotecan); cell cycle inhibitors (for example        flavopyridols); and biological response modifiers. Particular        compounds could include        N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide,        hemi L-Tartaric acid salt.

The compounds of formula I and the pharmaceutical compositionscomprising compounds of formula I may be administered by any meanssuitable for the condition to be treated, which may depend on the needfor site-specific treatment or quantity of drug to be delivered. Thecompounds may be administered in a dosage range of about 0.05 to 200mg/kg/day, preferably less than 100 mg/kg/day, in a single dose or in 2to 4 divided doses.

Topical administration is generally preferred for skin-related diseases,and systematic treatment is preferred for cancerous or pre-cancerousconditions, although other modes of delivery are contemplated. Forexample, the compounds and compositions may be delivered oraly, such asin the form of tablets, capsules, granules, powders, or liquidformulations including syrups; topically, such as in the form ofsolutions, suspensions, gels or ointments; sublingually; bucally;parenterally, such as by subcutaneous, intravenous, intramuscular orintrasternal injection or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasallysuch as by inhalation spray; topically, such as in the form of a creamor ointment; rectally such as in the form of suppositories; orliposomally.

Dosage unit formulations containing non-toxic, pharmaceuticallyacceptable carriers, vehicles or diluents may be administered. Thecompounds and compositions may be administered in a form suitable forimmediate release or extended release. Immediate release or extendedrelease may be achieved with suitable pharmaceutical compositions or,particularly in the case of extended release, with devices such assubcutaneous implants or osmotic pumps. Further techniques forformulation and administration of the compounds and compositions of theinstant application may be found in “Remington's PharmaceuticalSciences,” 18^(th) Ed. (1990, Mack Publishing Co., Easton, Pa.).

Abbreviations

The following abbreviations are among those used herein:

-   -   Δ=heat    -   Ac=acetyl    -   AcOH=acetic acid    -   aq.=aqueous    -   ATP=adenosine triphosphate    -   BOP=benzotriazol-1-yloxytris(dimethylamino)-phosphonium    -   BSA=Bovine serum albumin    -   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCC=Dicyclohexylcarbodiimide    -   DCE=dichloroethane    -   DEAD=diethyl azodicarboxylate    -   DIBAL-H=diisobutylaluminum hydride    -   DIPEA=N,N-diisopropylethylamine    -   DMA=dimethylacetamide    -   DME=1,2-dimethoxyethane    -   DMF=dimethylformamide    -   DMSO=dimethylsulfoxide    -   DPPA=Diphenylphosphoryl azide    -   DTT=Dithiothreitol    -   EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride    -   EDTA=ethylenediamine tetracetic acid    -   Et=ethyl    -   Et₂O=diethyl ether    -   EtOAc=ethyl acetate    -   EtOH=ethanol    -   GST=gluetithione S-transferase    -   h=hours    -   Hexafluorophosphate    -   HOAt=1-hydroxy-7-azabenzotriazole    -   HOBt=1-hydroxybenzotriazole    -   Hünig's Base=N,N-diisopropylethylamine    -   KOtBu=potassium tert-butoxide    -   LC=liquid chromatography    -   LDA=lithium diisopropylamide    -   MBP=Myelin basic protein    -   mCPBA=m-chloropetroxybenzoic acid    -   Me=methyl    -   MeI=methyl iodide    -   MeOH=methanol    -   MS(ES)=Electro-Spray Mass Spectrometry    -   n-BuLi=n-butyllithium    -   Pd/C=palladium on activated charcoal    -   Ph=phenyl    -   PhCH₃=toluene    -   pTSA=para-toluenesulfonic acid    -   RT=retention time    -   rt=room temperature    -   sat.=saturated    -   t-Bu=tert.butyl    -   TCA=trichloroacetic acid    -   TEA=triethylamine    -   TFA=trifluoroactic acid    -   THF=tetrahydrofuran    -   TLC=thin layer chromatography    -   Tris-HCL=Tris[hydroxymethyl]aminomethane hydrochloride    -   Ts=tosyl    -   TsCl=tosyl chloride    -   TsOH=tosic acid

The following examples are provided to describe the invention in furtherdetail. These examples are intended to illustrate and not to limit theinvention. All temperatures are given in centigrade degrees (° C.)unless otherwise noted. The YMC Co., Ltd., a supplier of HPLC columns,is located in Kyoto, Japan, and may be reached through the Waters Co. inMilford, Mass.

EXAMPLE 1 Preparation of3-Cyano-4-(cyclohexylamino)-5-methylpyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (1E)

A. Preparation of 3-Methyl-1H-pyrrole-2,4-dicarboxylic acid diethylester (1A)

To a solution of ethyl isocyanoacetate (38.1 mL, 0.34 mol) and DBU (50.8mL, 0.34 mol) in THF (400 mL) at 50° C. was added a solution ofacetaldehyde (9.5 mL, 0.17 mol) in THF (100 mL) over 25 min. Thereaction mixture was stirred at 55° C. for 17 h, cooled to 25° C. andacetic acid (20 mL) was slowly added. The resulting mixture wasconcentrated in vacuo and the resulting residue was dissolved in ethylacetate (800 mL) and washed with HCl (1 N, 3×300 mL). The combinedaqueous washes were extracted with ethyl acetate (3×200 mL) and thecombined organic layer were washed with NaHCO₃ (sat. aq., 3×200 mL),water (100 mL) and brine (100 mL) and then concentrated in vacuo toafford a dark brown oil. Elution of this oil through a silica pad usingethyl acetate/hexanes (1:1) and the concentration in vacuo providedcompound 1A (16 g, 42% yield) as a yellow solid. HPLC: 100% at 3.536 min(retention time) (YMC S5 ODS column, 4.6×═mm, eluting with 10-90%aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 226.0 [M+H] ⁺.B. Preparation of 1-Amino-3-methyl-1H-pyrrole-2,4-dicarboxylic aciddiethyl ester (1B)

To a suspension of NaH (60% suspension in mineral oil, 213 mg, 5.33mmol) in DMF (15 mL) at 0° C. was added compound 1A (1.0 g, 4.44 mmol),portionwise. The reaction mixture was stirred at 0° C. for 5 min andthen warmed to 25° C. and stirred for an additional 1 h. The reactionmixture was then cooled to 10° C. and 2,4-dinitro-aminophenol (972 mg,4.88 mmol) was added in two portions. The resulting mixture was warmedto 25° C., stirred for 12 h, poured onto water (40 mL) anddichloromethane (50 mL), and the layers were separated. The aqueousphase was extracted with dichloromethane (3×20 mL), and the combinedorganic extracts were washed with NaOH (1N, 3×20 mL), water (20 mL), andbrine (20 mL) and then dried over MgSO₄, filtered, and concentrated invacuo. The resulting reddish-brown residue was further concentrated for12 h under high vacuum to yield 800 mg (75% yield) of compound 2B whichwas used without further purification. HPLC: 100% at 3.488 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 241.17 [M+H]⁺.C. Preparation of3-Cyano-1,4-dihydro-5-methyl-4-oxopyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (1C)

To a solution of 1-amino-3-methyl-1H-pyrrole-2,4-dicarboxylic aciddiethyl ester (1.08 g, 4.50 mmol) in toluene (15 mL) were added1,1-diethoxypropionitrile (2.02 mL, 1.93 g, 13.5 mmol) and TsOH-H₂O (171mg, 0.90 mmol). The reaction mixture was heated at reflux for 12 h andthen cooled to 25° C. DBU (0.18 mL, 0.822 g, 5.40 mmol) was added andthe resulting dark brown mixture was heated at 80° C. for 1 h and thencoded to room temperature. The reaction mixture was poured ontodichloromethane (50 mL) and NH₄Cl (sat. aq., 50 mL) and the layers wereseparated. The aqueous layer was extracted with dichloromethane (2×30mL) and the combined organic extracts were washed with water (30 mL),dried over MgSO₄, filtered and concentrated in vacuo. The crude productwas purified by silica gel column chromatography (10-30%methanol/dichloromethane) to provided 441 mg (40%) of compound 1C as abrown solid. HPLC: 100% at 3.383 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 246.09 [M+H]⁺.D Preparation of4-Chloro-3-cyano-5-methylpyrrolo[1,2-b]pyridazine-6-carboxylic acidethyl ester (1D)

A 15 mL round bottom flask containing the compound 1C (370 mg, 1.51mmol) was charged with POCl₃ (1 mL) and heated to 75° C. for 2 h. Thereaction mixture was concentrated in vacuo and the resulting yellowresidue was dissolved in dichloromethane (10 mL) and added, via pipette,to a saturated aqueous solution of NaCHO₃ with stirring at 0° C. Theheterogeneous mixture was stirred for 10 min at 0° C. then warmed toroom temperature and stirred for an additional 1h. The mixture waspoured into a separatory funnel and the layers were separated. Theaqueous phase was extracted with dichloromethane (2×20 mL) and thecombined organic extracts were washed with NaHCO₃ (sat. aq., 1×20 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The resultingresidue was dissolved in EtOAc (20 mL) and filtered through a pad ofsilica using EtOAc (100 mL) to wash the silica pad. The filtrate wasconcentrated in vacuo to afford compound 1D as a yellow solid which wasused without further purification. HPLC: 100% at 4.160 min (retentiontime) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueousmethanol over 4 min containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm).

E. Preparation of3-Cyano-4-(cyclohexylamino)-5-methylpyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (1E)

To a solution of compound 1D (20 mg, 0.076 mmol) in acetonitrile (1 mL)were added Et₃N (32 μL, 0.228 mmol) and cyclohexylamine (10 μL, 0.084mmol) and the reaction mixture was stirred at 25° C. After 24 h, anadditional 10 μL of cyclohexylamine was added and the reaction mixturewas stirred for an additional 1.5 h after which time it was poured ontoNaHCO₃ (sat. aq., 20 mL) and dichloromethane. The layers were separatedand the aqueous layer was extracted with dichloromethane (2×10 mL). Thecombined organic layers were washed with water (20 mL), dried overMgSO₄, filtered and concentrated in vacuo to yield 18 mg (75%) ofcompound 1E as a yellow solid, which was used without furtherpurification. HPLC: 100% at 4.60 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 327.2 [M+H]⁺.

EXAMPLE 2 Preparation of 3-Cyano-5-methyl-4-phenoxypyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester

To a solution of compound 1D (18 mg, 0.068 mmol) in acetonitrile (0.5mL) at room temperature was added Et₃N (21 uL, 0.205 mmol) and phenol (7mg, 0.075 mmol). The reaction mixture was stirred for 24 h and thenpoured onto dichloromethane (10 mL) and NaHCO₃ (sat. aq., 10 mL). Thelayers were separated, the aqueous phase was extracted withdichloromethane (3×5 mL), and the combined organic extracts were washedwith water, dried over MgSO₄, filtered, and concentrated in vacuo toafford compound 2 (15 mg, 68%) as a yellow solid. HPLC: 100% at 4.35 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 340.0 [M+NH₄]⁺.

EXAMPLE 3 Preparation of6-(Methoxymethyl)-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-3-carbonitrile(3C)

A. Preparation of3-Cyano-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (3A)

To a solution of compound 1D (26 mg, 0.10 mmol) in DMF (2 mL) were addedK₂CO₃ (138 mg, 1.00 mmol) and p-phenoxyaniline (20 mg, 0.11 mmol) at 25°C. The reaction mixture was stirred for 12 h and then diluted withdichloromethane (15 mL) and washed with water (10 mL) and brine (10 mL).The organic phase was dried over Na₂SO₄ and concentrated and theresulting residue was triturated with methanol to afford 31 mg (76%yield) of the desired compound as a yellow solid. HPLC: 100% at 4.62 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 413.12 [M+H]⁺.

Compound 3A can also be prepared as follows: To a solution of 1D (1.00g, 3.79 mmol) in THF (10 mL) were added 4-phenoxyaniline (0.84 g, 4.53mmol) and triethylamine (1.06 mL, 7.58 mmol). The reaction mixture washeated at 60° C. for 3 days, after which time it was cooled to roomtemperature and diluted with MeOH (50 mL). The resulting solids werefiltered, washed with MeOH and dried to yield 1.50 g (96% yield) of 3Aas a yellow powder.B. Preparation of6-(Hydroxymethyl)-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-3-carbonitrile(3B)

To a solution of compound 3A (41 mg, 0.10 mmol) in THF (2 mL) at −78° C.was added DIBAL-H (1.5 M in toluene, 0.13 mL, 0.20 mmol). The reactionmixture was stirred for 6 h at −78° C., warmed to 0° C. and stirred foran additional 2h. The reaction mixture was quenched by the addition ofmethanol (3 mL) and sat. aq. Na₂CO₃ (3 mL) and then poured ontodichloromethane (20 mL). The layers were separated, the aqueous phasewas extracted with dichloromethane (2×15 mL), and the combined organicextracts were dried over MgSO₄, filtered, and concentrated in vacuo.Purification via preparative HPLC (YMC S5 ODS 20-100 mm, eluting with30-100% aqueous methanol over 15 min containing 0.1% TFA, 20 mL/min)afforded 33 mg (90% yield) of compound 3B as a yellow solid. HPLC: 100%at 3.98 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 371.19 [M+H]⁺.

C. Preparation of6-(Methoxymethyl)-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-3-carbonitrile(3C)

To a solution of compound 3B (9.0 mg, 0.025 mmol) in DMF:THF (1:1, 1 mL)at 0° C. was added KOtBu (1.5 M in THF, 0.025 mL, 0.038 mmol). Afterstirring for 45° min at 0° C., methyl iodide (2 μL, 0.025 mmol) wasadded and the reaction mixture was stirred for an additional 1h, warmedto 25° C., and stirred for 3h. No reaction was observed during thistime. The reaction mixture was cooled once more to 0° C., additionalKOtBu (1.5 M in THF, 0.25 mL, 0.38 mmol) was added and the reactionmixture was stirred for 30 min, after which time additional methyliodide (20 μL, 0.25 mmol) was added. After stirring for an additional 2hat 0° C., the reaction was quenched by the addition of saturated aqueousNH₄Cl (10 mL) and dichloromethane (10 mL). The layers were separated,the aqueous phase was extracted with dichloromethane (2×10 mL) and thecombined organic extracts were dried over MgSO₄, filtered concentrated,and purified by preparative HPLC (YMC S5 ODS 20×100 mm, eluting with30-100% aqueous methanol over 15 min containing 0.1% TFA, 20 mL/min) toafford the desired product as a yellow semi-solid. HPLC: 100% at 4.27min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min,monitoring at 200 nm). MS (ES): m/z 385.21 [M+H]⁺.

EXAMPLE 4 Preparation of4-[(2-Chloro-4-iodophenyl)amino]-3-cyano-5-methylpyrrolo[1,2-b]pyridazine-6-carboxylicacid

To a solution of4-[(2-chloro-4-iodophenyl)-amino]-3-cyano-5-methylpyrrolo[1,2-b]pyridazine-6-carboxylicacid, ethyl ester (59 mg, 0.123 mmol, prepared as described inExample 1) in THF (1 mL) was added NaOH (1N, 1 mL). The reaction mixturewas stirred at 25° C. for 72 h and then poured onto NaHCO₃ (30 mL) andEtOAc (30 mL). The layers were separated and the aqueous phase wasacidified to pH=2 and extracted with dichloromethane (2×20 mL). Thecombined organic extracts were washed with brine, dried over MgSO₄,filtered and concentrated in vacuo to afford 20 mg (36% yield) ofcompound 4 which was used without further purification. ¹H NMR (DMSO-d₆)□8.99 (s, 1H), 8.18 (s, 1H), 8.03 (s, 1H), 7.97 (s, 1H), 7.75 (d, 1H),7.29 (d, 1H), 2.78 (s, 3H). HPLC: 100% at 4.04 min (retention time) (YMCS5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).

EXAMPLE 5 Preparation of4-[(2-Chloro-4-iodophenyl)amino]-3-cyano-5-methyl-N-(2-methylpropoxy)pyrrolo[1,2-b]pyridazine-6-carboxamide

To a solution of compound 4 (20 mg, 0.442 mmol) in THF:dichloromethane(1:1, 1 mL) were added isopropylhydroxylamine (7 mg, 0.053 mmol),Hunig's base (18 □L, 0.106 mmol) and PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) 28 mg, 0.531 mmol).The reaction mixture was stirred for 1h, concentrated in vacuo anddiluted with 10% HCl (15 mL) and Et₂O (15 mL). The layers were separatedand the organic phase was washed with 1N NaOH (15 mL) and brine (15 mL),dried over MgSO₄, filtered and concentrated in vacuo. The aqueous phasewas made basic by the addition of 1N NaOH and extracted with EtOAc (2×15mL). The organic extracts were dried over MgSO₄, filtered, concentratedin vacuo, and added to the combined organic layers of the firstextractions. Preparative HPLC (YMC S5 ODS 20×100 mm, eluting with30-100% aqueous methanol over 15 min containing 0.1% TFA, 20 mL/min)provided 1.1 mg of the compound 5. HPLC: 100% at 3.68 min (retentiontime) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueousmethanol over 4 min containing 0.1% TFA, 4 mL/min, monitoring at 220nm). MS (ES): m/z 524.02 [M+H] ⁺.

EXAMPLE 6 Preparation of3-Cyano-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[1,2-b]pyridazine-6-carboxylicacid

To a solution of3-cyano-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methylpyrrolo[1,2-b]pyridazine-6-carboxylicacid, ethyl ester (160 mg, 0.393 mmol, prepared as described inExample 1) in THF (2 mL) was added 1N NaOH (4 mL). The reaction mixturewas stirred at 25° C. for 2 days and then neutralized with 1M citricacid and poured onto dichloromethane. The organic phase was separatedand extracted with dichloromethane, and the combined organic extractswere dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresulting residue was purified via preparative HPLC (YMC S5 ODS 20'100mm, eluting with 30-100% aqueous methanol over 15 min containing 0.1%TFA, 20 mL/min) to afford 36 mg (39% yield) of compound 6. HPLC: 100% at3.33 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 380.24 [M+H]⁺.

EXAMPLE 7 Preparation of3-Cyano-4-[[5-[(methoxyamino)carbonyl]-2-methylphenyl]amino]-5-methyl-N-[(1S)-1-phenylethyl]pyrrolo[1,2-b]pyridazine-6-carboxamide

To a solution of compound 6 (19 mg, 0.05 mmol) in DMF (2 mL) were addedEDC (14.4 mg, 0.075 mmol), HOBt (10.1 mg, 0.075 mmol) and DIPEA (12.9mg, 0.10 mmol) and the reaction mixture was stirred for 30 min at 25° C.(S)-Methylbenzylamine (7.3 mg, 0.06 mmol) was then added and thereaction mixture was stirred for an additional 16h at 25° C. Thereaction was then diluted with dichloromethane and poured into water.The layers were separated and the organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified viapreparative HPLC (YMC S5 ODS 20×100 mm, eluting with 30-100% aqueousmethanol over 15 min containing 0.1% TFA, 20 mL/min) to afford 21 mg(87% yield) of compound 7 as a yellow semi-solid. HPLC: 100% at 3.79 min(retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90%aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min,monitoring at 220 nm). MS (ES): m/z 483.36 [M+H]⁺.

EXAMPLE 8 Preparation of6-Formyl-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-3-carbonitrile

To a solution of compound 3B (266 mg, 0.72 mmol) in dichloromethane (30mL) was added MnO₂ (200 mg, 2.0 mmol). The reaction mixture was heatedat 60° C. for 3 h, cooled to 25° C., diluted with dichloromethane andfiltered through Celite. The filtrate was concentrated in vacuo andpurified by column chromatography on silica gel (0.5% MeOH/CH₂Cl₂) toafford 238 mg (90% yield) of compound 8 as a yellow solid. HPLC; 100% at3.37 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4mL/min, monitoring at 220 nm). MS (ES): m/z 369.08 [M+H] ⁺.

EXAMPLE 9 Preparation of3-Cyano-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-6-carboxylicacid

To a solution of compound 3A (1.50 g, 3.64 mmol) in THF (50 mL) wereadded NaOH (1 M, 20.0 mL) and EtOH (25 mL). The reaction was heated at80° C., effectively evaporating the THF, and, after 1h, the reactionmixture became homogeneous. Heating was continued for an additional 6h,after which time the reaction was cooled to rt and neutralized with HCl(1 M, 20.0 mL). The resulting solids were filtered, washed with waterand dried to afford compound 9 (1.33 g, 95% yield) as a yellow solid.HPLC: 100% at 1.84 min (retention time) (YMC S5 ODs column, 4.6×50 mmeluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 4mL/min, monitoring at 220 nm). MS (ES): m/z 489.0 [M+H]⁺.

EXAMPLE 10 Preparation of an Amide Library Preparation of3-Cyano-5-methyl-4-[(4-phenoxyphenyl)amino]-N-phenylpyrrolo[1,2-b]pyridazine-6-carboxamide

To a solution of compound 9 (11.5 mg, 0.030 mmol) and HOAt (6.1 mg,0.045 mmol) in THF (0.60 mL) was added a solution of aniline (14 mg,0.15 mmol) in THF (0.15 mL) followed by a solution of EDC (11.5 mg, 0.06mmol) in chloroform (0.30 mL). The reaction mixture was heated at 60° C.overnight and then cooled to rt and diluted with MeOH (0.4 mL). Theresulting mixture was purified by elution through a SCX/SAC cartridge(500 mg/500 mg) SCX SAX silica bound ionexchange cartridges supplied byUnited Chemical Technologies, Inc., Bristol, Pa., with MeOH, followed byconcentration of the solvent in vacuo, to afford 13.2 mg (96% yield) ofcompound 10 as a yellow solid. HPLC: 100% at 2.05 min (retention time)(YMC S5 ODS column 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutescontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS(ES): m/z 460.0 [M+H]⁺.

The above procedure was utilized to prepare a library of 68 amidecompounds by substituting other amines for the aniline reactant.Compounds were purified using the above method or by preparative HPLC(Shimadzu VP-ODS 20.0×50.0 mm eluting with 25-90% MeOH/H₂O over 7minutes containing 0.1% TFA, 10 mL/min, monitoring at 220 nm).

EXAMPLE 11 Preparation of6-Amino-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-3-carbonitrile(11B)

A. Preparation of[3-Cyano-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazin-6-yl]carbamicacid, phenylmethyl ester (11A)

To a solution of compound 9 (192 mg, 0.50 mmol) in dioxane (anhydrous, 4mL) under an N₂ atmosphere were added triethylamine (0.140 mL, 1.00mmol) and DPPA (0.216 mL, 1.00 mmol), and the mixture was stirredovernight. Benzyl alcohol (0.310 mL, 3.00 mmol) was then added and thereaction mixture was heated at 75° C. for 4 h, concentrated in vacuo andpurified by column chromatography on silica gel. (20 to 30%EtOAc/hexanes) to yield compound 11A as a yellow oil (172 mg, 70%).HPLC: 100% at 4.01 min (retention time) (YMC S5 ODS column, 4.6×50 mmeluting with 10-90% MeOH/H₂O over 4 minutes containing 0.1% TFA; 4mL/min, monitoring at 220 nm). MS (ES): m/z 490.0 [M+H]⁺.

B. Preparation of6-Amino-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-3-carbonitrile(11B)

To a solution of compound 11A (40 mg, 0.082 mmol) in MeOH (4 mL) wasadded Pd/C (12 mg), and the reaction mixture was stirred under hydrogen(1 atm) for 30 minutes, after which time HCl (4M in dioxane, 0.1 mL) wasadded. The reaction mixture was filtered and the filtrate concentratedin vacuo to provide 32 mg of compound 11B as an orange solid(quantitative yield as HCl salt). HPLC: 100% at 2.90 min (retentiontime) (YMC S5 ODS column, 4.6×50 mm eluting with 10-90% McOH/H₂O over 4minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). MS (ES):m/z 356.0 [M+H]⁺.

EXAMPLE 12 Preparation ofN-[3-Cyano-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazin-6-yl]acetamide

To a solution of compound 11B (HCl salt, 32 mg, 0.082 mmol) in THF (2mL) was added acetic anhydride (11 mg, 0.11 mmol) followed bytriethylamine (33 mg, 0.33 mmol) and the reaction was stirred at rt for30 min. After quenching with MeOH, the reaction mixture was stirred foran additional 30 min, concentrated in vacuo and purified by flashchromatography on silica gel (40 to 50% EtOAc/dichloromethane) tofurnish compound 12 as a yellow oil (30 mg, 92% yield). HPLC: 100% at3.46 min (retention time) (YMC S5 ODS column, 4.6×50 mm eluting with10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 4 mL/min, monitoringat 220 nm). MS (ES): m/z 398.0 [M+H]⁺.

EXAMPLE 13 Preparation of3-(Aminomethyl)-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-6-carboxylicacid

To a solution of compound 9 (27 mg, 0.070 mmol) in MeOH:THF (2:1 v/v, 6ml) was added TFA (30 mg) followed by Pd/C (10 mg). The reaction mixturewas stirred under hydrogen (1 atm) overnight and then filtered through apad of Celite. The filtrate was concentrated in vacuo and the residuewas purified by several azeotropic distillations with MeOH to removeexcess TFA. This procedure afforded compound 13 as a yellow solid (35mg, quantitative). HPLC: 100% at 2.96 min (retention time) (YMC S5 ODScolumn, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing0.1% TFA; mL/min, monitoring at 220 nm). MS (ES): m/z 389.0 [M+H]⁺.

EXAMPLE 14 Preparation of3-[(Acetylamino)methyl]-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazine-6-carboxylicacid

To a solution of compound 13 (10 mg, 0.02 mmol) in THF was addedtriethylamine (1 drop, ˜10 mg) followed by acetic anhydride (1 drop, ˜10mg). The reaction was stirred at rt for 10 min and then concentrated invacuo. The residue was redissolved in THF, and NaOH (1M, 2 drops) wasadded. The resulting mixture was stirred at rt for 2 hours, neutralizedwith HCl (1M) and purified by preparative HPLC (Shimadzu VP-ODS20.0×50.0 mm eluting with 25-90% MeOH/H₂O over 7 minutes containing 0.1%TFA, 10 mL/min, monitoring at 220 nm) to give compound 14 as a yellowsolid (7 mg, 81% yield). HPLC: 100% at 3.46 min (retention time) (YMC S5ODS column, 4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutescontaining 0.1% TFA; 4 mL/min, monitoring at 220 nm). MS (ES): m/z 431.0[M+H]⁺.

EXAMPLE 15 Preparation ofN-[3-Cyano-5-methyl-4-[(4-phenoxyphenyl)amino]pyrrolo[1,2-b]pyridazin-6-yl]-N′-methylurea

A solution of compound 9 (19 mg, 0.05 mmol), triethylamine (0.014 mL,0.10 mmol) and DPPA (0.022 mL, 0.10 mmol) in dry dioxane (1 mL) wasstirred under N₂ for 12h. The reaction was then heated to 80° C. for 1 hand then allowed to cool to 25° C. on standing. Methylamine (2.0 M THFsolution, 0.30 mL, 0.60 mmol) was added and the reaction was stirred at25° C. for 1 h, concentrated in vacuo and purified by flashchromatography on a silica gel column (50 to 70% EtOAc/dichloromethane)to give compound 15 (15 mg, 73%) as a yellow solid. HPLC: 100% at 3.44min (retention time) (YMC S5 ODS column, 4.6×50 mm eluting with 10-90%MeOH/H₂O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220nm). MS (ES): m/z 413.0 [M+H]⁺.

EXAMPLE 16 Preparation of3-Cyano-5-hydroxymethyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (16C)

A. 5-Bromomethyl-4-chloro-3-cyano-pyrrolo[1,3-b]pyridazine-6-carboxylicacid ethyl ester (16A)

A suspension of compound 1D (79 mg, 0.30 mmol), NBS (59 mg, 0.33 mmol)and benzoyl peroxide (5 mg, 0.02 mmol) in CCl₄ (2 mL) was heated at 77°C. for 3 hours. After cooling to room temperature, the reaction waspurified by a short silica gel column (eluted with CH₂Cl₂) to givecompound 16A as a yellow solid (102 mg, 99%).B.4-Chloro-3-cyano-5-hydroxymethyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (16B)

To a solution of compound 16A (102 mg, 0.30 mmol) in THF (12 mL) wasadded water (3 mL) dropwise. The reaction was kept at room temperaturefor 3 days and then heated to 50° C. for 3 hours. Upon cooling to roomtemperature, NaHCO₃ (70 mg) was added to the reaction mixture. Thereaction was concentrated to dryness, redissolved in CH₂Cl₂ andfiltered. The filtrate was concentrated to give compound 16B as a yellowsolid (84 mg, 100%). This compound was used in the following stepswithout further purification.

C.3-Cyano-5-hydroxymethyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (16C)

A solution of compound 16B (84 mg, 0.30 mmol), 4-phenoxyaniline (72 mg,0.39 mmol) and triethylamine (0.083 mL, 0.60 mmol) in THF (2.5 mL) washeated at 70° C. for 30 min. After cooled to room temperature, thereaction was concentrated to about 0.5 mL, diluted with MeOH (2 mL) andfiltered. The solid was washed with MeOH and dried to give compound 16Cas yellow solid (118 mg, 92%). HPLC: 92% at 2.12 min (retention time)(Prime Sphere 5u C18-HC column. 4.6×30 mm eluting with 10-90% MeOH/H₂Oover 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). MS(ES): m/z 429.0 [M+H]⁺.

EXAMPLE 17 Preparation of3-Cyano-5-methoxymethyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (17B)

A.4-Chloro-3-cyano-5-methoxymethyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (17A)

To a solution of compound 16A (31 mg, 0.09 mmol) in 1:1 MeOH:CH₂Cl₂ (2mL) was added NaHCO₃ (30 mg, 0.36 mmol). The reaction was kept at roomtemperature for 3 h, heated to 70° C. for 1 h, cooled to roomtemperature, concentrated to dryness, redissolved in CH₂Cl₂ andfiltered. The filtrate was concentrated to give compound 17A as a yellowsolid (26 mg, 98%).

B.3-Cyano-5-methoxymethyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (17B)

Compound 17B was made in accordance with the procedure described inExample 16C. HPLC: 96% at 2.24 min (retention time) (PrimeSphere 5 uC18-HC column, 4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutescontaining 0.1% TFA; 5 mL/min, monitoring at 220 nm). MS (ES): m/z 443.0[M+H]⁺.

EXAMPLE 18 Preparation of3-Cyano-5-formyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (18)

To a solution of compound 16C (21.4 mg, 0.05 mmol) in chloroform (1 mL)was added MnO₂ (<5 micron, activated, 17 mg, 0.20 mmol). The reactionwas heated at 55° C. overnight, cooled to room temperature and purifiedby flash chromatography on a silica gel column (0-2% EtOAc/CH₂Cl₂) togive compound 18 as a yellow solid (20 mg, 94%). HPLC: 94% at 2.20 min(retention time) (PrimeSphere 5u C18-HC column, 4.6×30 mm eluting with10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoringat 200 nm). MS (ES): m/z 427.0 [M+H]⁺.

EXAMPLE 19 Preparation of1-[3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-yl]-3-(2-morpholin-4-yl-ethyl)-urea(19-1) &5-Methyl-6-(5-oxo-4,5-dihydro-tetrazol-1-yl)-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile(19-2)

A solution of compound 9 (115 mg, 0.30 mmol), triethylamine (0.063 mL,0.45 mmol) and DPPA (0.97 mL, 0.45 mmol) in dioxane (5 mL) was stirredovernight. The next day TMS-azide (0.08 mL, 0.60 mmol) was added and thereaction temperature was brought to 80° C. The reaction was heated at80° C. for 2 hours, cooled to room temperature and4-(2-aminoethyl)morpholine (0.079 mL, 0.06 mmol) was added. The reactionwas stirred at room temperature for 1 h, concentrated and purified byflash chromatography on a sila gel column (3-6% MeOH/CH₂Cl₂) to give amixture of compounds 19-1 and 19-2 as a yellow oil. This oil wasrecrystalized from MeOH to give compound 19-1 as a yellow solid (116 mg,76%). 19-1: HPLC: 97% at 3.11 min (retention time) (YMC S5 ODS column,4.6×50 mm eluting with 10-90% MeOH/H₂O over 4 minutes containing 0.1%TFA, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 512.0 [M+H]⁺.

The mother liquor from the above recrystallization was passed through aSCX cartridge (500 mg) and eluted with MeOH (5 mL). The elutant wasconcentrated to give compound 19-2 as a yellow solid (9 mg, 7%). 19-2:HPLC: 94% at 1.93 min (retention time) (PrimeSphere 5u C18-HC column,4.6×30 mm eluting with 10-90% MeOH/H₂O over 2 minutes containing 0.1%TFA; 5 mL/min, monitoring at 220 nm). MS (ES): m/z 424.0 [M+H]⁺.

EXAMPLES 20 TO 144

Further compounds of the present invention were prepared by proceduresanalogous to those described above. Table 1 provides the name andstructure or representative compounds and their retention times, as wellas the Example number of the procedure on which the preparation of thecompound was based. The chromatography techniques used to determine theretention times of the compounds listed in Table 1 are as follows:

-   -   LCMS=YMC S5 ODS column, 4.6×50 mm eluting with 10-90% MeOH/H₂O        over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220        nm.    -   LCMS*=YMC S5 ODS column, 4.6×50 mm eluting with 10-90% MeOH/H₂O        over 2 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220        nm.    -   LCMS-1=PrimeSphere 5u C18-HC column, 4.6×30 mm eluting with        10-90% MeOH/H₂O over 2 minutes containing 0.1% TFA; 5 mL/min,        monitoring at 220 nm.    -   LC=YMC S5 S5 ODS column 4.6×50 mm eluting with 10-90% MeOH/H₂O        over 4 minutes containing 0.2% phosphate acid, 4 mL/min,        monitoring at 220 nm.    -   LC*=YMC S5 ODs column 4.6×50 mm eluting wiht 10-90% MeOH/H₂O        over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,        monitoring at 220 nm.

The molecular mass of the compounds listed in Table 1 were determined byMS (ES) by the formula m/z.

TABLE 1 Retention Time Min./ Ex. Molecular Proc. No. Compound StructureCompound Name Mass of Ex. 20

4-(6-Amino-1H- indazol-1-yl)-3- cyano-5- methylpyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 3.42 LC [M + H]⁺ = 361.0 121

4-(6-Amino-1H- indazol-1-yl)-3- cyano-5,7- dimethylpyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 3.59 LC [M + H]⁺ = 375.0 122

3-Cyano-4-(1-H- imidazol-1-yl)-5- methylpyrrolo]1,2- b]pyridazine-6-carboxylic acid, ethyl ester 2.79 LC [M + H]⁺ = 296.0 1 23

3-Cyano-4- (dimethylamino)- 5,7- dimethylpyrrolo[1,2- b]pyridazine-6-carboxylic acid, ethyl ester 4.27 LC [M + H]⁺ = 287.0 1 24

3-Cyano-4-(1-H- indazol-6-ylamino)- 5,7- dimethylpyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 4.06 LC [M + H]⁺ = 375.0 125

3-Cyano-5-methyl- 4-[(2-methyl-1H- indol-5- yl)amino]pyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 4.22 LC [M + H]⁺ = 374.0 126

3-Cyano-5-methyl- 4-(phenylamino)- pyrrolo[1,2-b]py- ridazine-6-car-boxylic acid, ethyl ester 4.07 LC [M + H]⁺ = 321.0 1 27

3-Cyano-5-methyl- 4-[(2-methyl-1H- indol-5- yl)oxy]pyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 3.80 LCMS [M + H]⁺ = 375.02 28

3-Cyano-5-methyl- 4-[[1- (phenylmethyl)-1H- indazol-5-yl]amino]pyrrolo[1,2- b]pyridazine-6- carboxylic acid, ethyl ester 4.31LC [M + H]⁺ = 451.0 1 29

3-Cyano-5-methyl- 4-(1H-indazol-1- yl)pyrrolo[1,2- b]pyridazine-6-carboxylic acid, ethyl ester 4.04 LC [M + H]⁺ = 346.0 1 30

3-Cyano-4-[(4- fluoro-2-methyl-1H- indol-5-yl)oxy]-5- methylpyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 3.86 LC [M + H]⁺ = 393.0 131

3-Cyano-4-[[2- fluoro-5- [(methyoxyamino)car- bonyl]phenyl]- amino]-5-methylpyrrolo[1,2- b]pyridazine-6- carboxylic acid, ethyl ester 4.23 LC[M + H]⁺ = 412.0 1 32

3-Cyano-4-[[5- [(methoxyamino)car- bonyl]-2- methylphenyl]- amino]-5-methylpyrrolo[1,2- b]pyridazine-6- carboxylic acid, ethyl ester 4.19 LC[M + H]⁺ = 408.0 1 33

4-[(4-Bromo-2- fluorophenyl)amino]- 3-cyano-5- methylpyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 4.32 LC 1 34

4-[(4-Chloro-2- iodophenyl)amino]- 3-cyano-5- methylpyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 4.37 LC [M + H]⁺ = 481.0 135

4-[(2-Chloro-4- iodophenyl)amino]- 3-cyano-5- methylpyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 4.51 LC [M + Na⁺]⁺ = 503.036

3-Cyano-4-[[2- fluoro-5- [(methoxyamino)car- bonyl]phenyl]- amino]-5-methylpyrrolo[1,2- b]pyridazine-6- carboxylic acid, ethyl ester 4.24 LC[M + H]⁺ = 412.0 1 37

3-Cyano-N-ethyl-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazine-6- carboxamide 1.85 LC* [M + H]⁺ = 412.0 10 38

1-[[3-Cyano-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]-4- methylpiperazine 1.53 LC* [M + H]⁺ =467.0 10 39

3-Cyano-5-methyl- 4[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazine-6- carboxamide 1.75 LC* [M + H] = 384.0 10 40

3-Cyano-N,5- dimethyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazine-6- carboxamide 1.79 LC* [M + H]⁺ = 398.0 10 41

3-Cyano-N,N,5- trimethyl-4-[(4- phenoxy- phenyl)amino]pyrrolo[1,2-b]pyridazine-6- carboxamide 1.78 LC* [M + H]⁺ = 412.0 10 42

N-Butyl-3-cyano-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazine-6- carboxamide 2.00 LC* [M + H]⁺ = 440.0 10 43

3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino]-N- (phenylmethyl)pyrrolo[1,2-b]pyridazine- 6-carboxamide 2.00 LC* [M + H]⁺ = 474.0 10 44

3-Cyano-N-[(4- methoxyphenyl) methyl]-5-methyl-4- [(4-phenoxyphenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 1.98 LC* [M + H]⁺ = 504.010 45

3-Cyano-N-[(3- methoxyphenyl) methyl -5-methyl-4- [(4-phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 2.10 LC* [M + H]⁺= 504.0 10 46

N-[(4- Chlorophenyl)methyl]- 3-cyano-5-methyl- 4-[(4- phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 2.09 LC* [M + H]⁺= 508.0 10 47

N-[(3- Chlorophenyl)methyl]- 3-cyano-5-methyl- 4-[(4- phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 2.08 LC* [M + H]⁺= 508.0 10 48

N-[(2- Chlorophenyl)methyl]- 3-cyano-5-methyl- 4-[(4- phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 2.06 LC* [M + H]⁺= 508.0 10 49

3-Cyano-5-methyl- 4[(4- phenoxy- phenyl)amino]- N-(2-phenylethyl)pyrrolo [1,2-b]pyridazine-6- carboxamide 2.04 LC* [M + H]⁺ =488.0 10 50

3-Cyano-N-(2- furanylmethyl)-5- methyl-4-[(4- phenoxy-phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 1.92 LC* [M + H]⁺= 464.0 10 51

3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino]- N-(2-thienylmethyl)pyrrolo [1,2-b]pyridazine- 6-carboxamide 1.97 LC* [M + H]⁺= 480.0 10 52

3-Cyano-N- cyclopropyl-5- methyl-4-[(4- phenoxy- phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 1.86 LC* [M + H]⁺ = 424.0 10 53

3-Cyano-N- cyclopentyl-5- methyl-4-[(4- phenoxy- phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 1.99 LC* [M + H]⁺ = 452.0 10 54

3-Cyano-N- cyclohexyl-5- methyl-4-[(4- phenoxy- phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 2.07 LC* [M + H]⁺ = 466.0 10 55

3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino]- N-[(tetrahydro-2-furanyl)methyl]pyrr- olo[1,2-b]pyridazine- 6-carboxamide 1.89 LC* [M +H]⁺ = 468.0 10 56

3-Cyano-N-(2- ethoxyethyl)-5- methyl-4-[(4- phenoxy- phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 1.90 LC* [M + H]⁺ = 456.0 10 57

3-Cyano-5-methyl- N-(2-phenoxyethyl)- 4-[(4- phenoxy-phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 2.05 LC* [M + H]⁺= 504.0 10 58

3-Cyano-N-(2,3- dihydroxypropyl)-5- methyl-4-[(4- phenoxy- phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 1.69 LC* [M + H]⁺ = 458.0 10 59

3-Cyano-N-(6- hydroxyhexyl)-5- methyl-4-[(4- phenoxy- phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 1.87 LC* [M + H]⁺ = 484.0 10 60

N-[2- (Acetylamino)ethyl]- 3-cyano-5-methyl-4- [(4- phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.74 LC* [M + H]⁺= 469.0 10 61

3-Cyano-5-methyl- N-[3-(2-oxo-1- pyrrolidinyl)propyl]- 4-[(4- phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.81 LC* [M + H]⁺= 509.0 10 62

3-Cyano-N,N- diethyl-5-methyl-4- [(4- phenoxy- phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 1.90 LC* [M + H]⁺ = 440.0 10 63

1-[[3-Cyano-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]pyrrolidine 1.88 LC* [M + H]⁺ = 438.0 10 64

1-[[3-Cyano-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]piperidine 1.96 LC* [M + H]⁺ = 452.0 10 65

4-[[3-Cyano-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]morpholine 1.76 LC* [M + H]⁺ = 454.0 10 66

1-[[3-Cyano-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]-4- hydroxypiperidine 1.74 LC* [M + H]⁺ =468.0 10 67

1-[[3-Cyano-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]-4- (hydroxymethyl)piper- idine 1.76 LC* [M +H]⁺ = 482.0 10 68

1-Acetyl-4-[[3- cyano-5-methyl-4- [(4- phenoxy- phenyl)amino]pyrrolo[1,2- b]pyridazin-6- yl]carbonyl]piper- azine 1.69 LC* [M + H]⁺ =495.0 10 69

4-[[3-Cyano-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]-1- piperiazinecarboxylic acid, ethyl ester1.85 LC* [M + H]⁺ = 525.0 10 70

1-[[3-Cyano-5- methyl-4-[(4- phenoxy- phenyl)amino]pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]-3- piperidinecarbox- amide 1.72 LC* [M + H]⁺= 495.0 10 71

(2S)-1-[[3-Cyano-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]-2- (hydroxymethyl)pyrr- olidone 1.79 LC*[M + H]⁺ = 468.0 10 72

1-[[3-Cyano-6- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]-3- hydroxypyrrolidine 1.70 LC* [M + H]⁺ =454.0 10 73

3-Cyano-N,N-bis(2- hydroxyethyl)-5- methyl-4-[(4- phenoxy- phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 1.62 LC* [M + H]⁺ = 472.0 10 74

N-(2-Chlorophenyl)- 3-cyano-5-methyl-4- [(4- phenoxy- phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 2.09 LC* [M + H]⁺ = 494.0 10 75

N-(3-Chlorophenyl)- 3-cyano-5-methyl-4- [(4- phenoxy- phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 2.18 LC* [M + H]⁺ = 494.0 10 76

N-(4-Chlorophenyl)- 3-cyano-5-methyl-4- [(4- phenoxy- phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 2.17 LC* [M + H]⁺ = 494.0 10 77

3-Cyano-N-(4- methoxyphenyl)-5- methyl-4-[(4- phenoxyphentl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 2.03 LC* [M + H]⁺ = 490.0 10 78

3-Cyano-5-methyl- N-(4- phenoxyphenyl)-4- [(4-phenoxy- phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 2.26 LC* [M + H]⁺ = 552.0 10 79

N-[4- (Acetylamino)- phenyl]- 3-cyano-5-methyl- 4-[(4- phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.91 LC* [M + H]⁺= 517.0 10 80

3-Cyano-5-methyl- N-1-naphthalenyl-4- [(4- phenoxy-phenyl)amino]pyrrolo[1,2- b]pyridazine-6- carboxamide 2.09 LC* [M + H]⁺= 510.0 10 81

1-[[3-Cyano-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]-4- phenylpiperazine 2.02 LC* [M + H]⁺ =529.0 10 82

1-[[3-Cyano-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]-4- (phenylmethyl)piper- azine 1.64 LC* [M +H]⁺ = 543.0 10 83

3-Cyano-N-[2- (dimethylamino)ethyl]- 5-methyl-4-[(4- phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.60 LC* [M + H]⁺= 455.0 10 84

3-Cyano-N-[2- (diethylamino)ethyl]- 5-methyl-4-[(4- phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carfboxamide 1.62 LC* [M +H]⁺ = 483.0 10 85

N-[2-[Bis(1- methylethyl)amino] ethyl]-3-cyano-5- methyl-4-[(4- phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.66 LC* [M + H]⁺= 511.0 10 86

3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino]- N-[2-(1-pyrrolidinyl)ethyl] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.62 LC*[M + H]⁺ = 481.0 10 87

3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino]- N-[2-(1-piperidinyl)ethyl] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.64 LC*[M + H]⁺ = 495.0 10 88

3-Cyano-5-mnethyl- 4-[(4- phenoxy- phenyl)amino]- N-[2-(4-morpholinyl)ethyl] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.60 LC*[M + H]⁺ = 497.0 10 89

3-Cyano-5-methyl- N-[3-(4- morpholinyl)propyl]- 4-[(4-phenopxyphenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.60 LC*[M + H]⁺ = 511.0 10 90

3-Cyano-N-[3- (dimethylamino)pro- pyl]-5-methyl-4-[(4- phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.62 LC* [M + H]⁺= 469.0 10 91

3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino]- N-[1-(phenylmethyl)-34- pyrrolidinyl]pyrrolo [1,2-b]pyridazine-6- carboxamide1.71 LC* [M + H]⁺ = 543.0 10 92

3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino]- N-[1- (phenylmethyl)-4-piperidinyl]pyrrolo[1, 2-b]pyridazine-6- carboxamide 1.71 LC* [M + H]⁺ =557.0 10 93

3-Cyano-N-(1-ethyl- 3-piperidinyl)-5- methyl-4-[(4- phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.65 LC* [M + H]⁺= 495.0 10 94

3-Cyano-N-[(1- ethyl-2- pyrrolidinyl)methyl]- 5-methyl-4-[(4-phenoxyphenyl(amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.65 LC*[M + H]⁺ = 495.0 10 95

3-Cyano-5-methyl- 4-[(4- phenopxyphenyl)amino]- N-(2- pyridinylmethyl)pyrrolo[1,2- b]pyridazine-6- carboxamide 1.63 LC* [M + H]⁺ = 475.0 10 96

3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino]- N-(3- pyridinylmethyl)pyrrolo[1,2- b]pyridazine-6- carboxamide 1.61 LC* [M + H]⁺ = 475.0 10 97

3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino]- N-(4- pyridinylmethyl)pyrrolo[1,2- b]pyridazine-6- carboxamide 1.61 LC* [M + H]⁺ = 475.0 10 98

3-Cyano-N-[2-(1H- imidazol-4-yl)ethyl]- 5-methyl-4-[(4- phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.61 LC* [M + H]⁺= 478.0 10 99

3-Cyano-N-[3-(1H- imidazol-1- yl)propyl]-5-methyl- 4-[(4- phenoxy-phenyl)amino] pyrrolo[1,2- b]pyridazine-6- carboxamide 1.62 LC* [M + H]⁺= 492.0 10 100

3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino]- N-3-pyridinylpyrrolo[1,2- b]pyridazine-6- carboxamide 1.70 LC* [M + H]⁺ =461.0 10 101

3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino]- N-2-pyridinylpyrrolo[1,2- b]pyridazine-6- carboxamide 1.74 LC* [M + H]⁺ =461.0 10 102

3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino]- N-3-quinolinylpyrrolo[1, 2-b]pyridazine-6- carboxamide 1.96 LC* [M + H]⁺ =511.0 10 103

3-Cyano-N-ethyl-5- methyl-4-[(4- phenoxyphenyl)amino] pyrrolo[1,2-b]pyridazine-6- carboxamide 1.85 LC* [M + H]⁺ = 412.0 10 104

(2R)-1-[[3-Cyano-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]-2- (hydroxymethyl) pyrrolidine 1.79 LC* [M +H]⁺ = 468.0 10 105

3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino]- N- phenylpyrrolo[1,2-b]pyridazine-6- carboxamide 2.05 LC* [M + H]⁺ = 460.0 10 106

1-[[3-Cyano-5- methyl-4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbonyl]-4- methylpiperazine 1.53 LC* [M + H]⁺ =467.0 10 107

3-Cyano-5-methyl- 4-[(3- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 2.01 LCMS* [M + H]⁺ = 413.010 108

4-[[4-(4- Chlorophenoxy)phenyl] amino]-3-cyano- 5-methylpyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 2.13 LCMS* [M + H]⁺ = 447.010 109

3-Cyano-5-methyl- 4-[[4-(phenyl- amino)phenyl] amino]pyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 1.95 LCMS* [M + H]⁺ = 412.010 110

3-Cyano-5-methyl- 4-[[4- (phenylmethyl)phenyl] amino]pyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 2.05 LCMS* [M + H]⁺ = 411.010 111

4-[(4- Benzoylphenyl)amino]- 3-cyano-5- methylpyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 1.91 LCMS* [M + H]⁺ = 425.010 112

4-[(3- Benzoylphenyl)amino]- 3-cyano-5- methyl-pyrrolo[1,2-b]pyridazine-6- carboxlylic acid, ethyl ester 1.92 LCMS* [M + H]⁺ =425.0 10 113

3-Cyano-4- (diethylamino)-5- methylpyrrolo[1,2- b]pyridazine-6-carboxylic acid, ethyl ester 1.85 LCMS* [M + H]⁺ = 301.0 10 114

3-Cyano-5-methyl- 4-(4- phenoxyphenoxy)pyrr- olo[1,2- b]pyridazine-6-carboxylic acid, ethyl ester 2.19 LCMS* [M + H]⁺ = 414.0 10 115

3-Cyano-5-methyl- 4-[[(4- phenoxyphenyl)methyl] amino]pyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 4.20 LCMS [M + H]⁺ = 427.010 116

4-[(4- Butylphenyl)amino]- 3-cyano-5- methylpyrrolo[1,2- b]pyridazine-6-carboxylic acid, ethyl ester 2.10 LCMS* [M + H]⁺ = 377.0 10 117

3-Cyano-4-[[4-(1,1- dimethylethyl)- phenyl]amino]-5- methylpyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 2.07 LCMS* [M + H]⁺ = 377.010 118

4-([1,1′-Biphenyl]-4- ylamino)-3-cyano-5- methylpyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 2.04 LCMS* [M + H]⁺ = 397.010 119

3-Cyano-4-[(9-ethyl- 9H-carbazol-3- yl)amino]-5- methylpyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 2.05 LCMS* [M + H]⁺ = 438.010 120

3-Cyano-5-methyl- 4-[[4- (phenylmethoxy)phenyl] amino]- pyrrolo[1,2-b]pyridazine-6- carboxylic acid, ethyl ester 2.03 LCMS* [M + H]⁺ = 427.010 121

[3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbamic acid, methyl ester 3.65 LCMS* [M + H]⁺ =414.0 11A 122

[3-Cyano-5-methyl- 4-[(4- phenoxy- phenyl)amino] pyrrolo[1,2-b]pyridazin-6- yl]carbamic acid, 1,1-dimethyl ester 3.99 LCMS [M + H]⁺ =456.0 11A 123

3-Cyano-4-(1H- indazol-6-ylamino)- 5-methylpyrrolo[1,2- b]pyridazine-6-carboxylic acid, ethyl ester 3.79 LC [M + H]⁺= 361.13 1 124

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino) pyrrolo[1,2-b]pyridazin-6-yl]-3- phenyl-urea 3.90 LCMS [M + H]⁺ = 475.0 19 125

4-[6-(4-Bromo- phenoxy)-pyridin-3- ylamino]-3-cyano-5-methyl-pyrrolo[1,2- b]pyridazine-6- carboxylic acid ethyl ester 4.01LCMS [M + H]⁺ = 492.0 1 126

3-Cyano-5-methyl- 4-[4-(pyrimidin-2- yloxy)- phenylamino]- pyrrolo[1,2-b]pyridazine-6- carboxylic acid ethyl ester 3.38 LC [M + H]⁺ = 415.0 1127

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- benzamide 1.94 LCMS-1 [M + H]⁺ = 460.0 12 128

3-Cyano-5-methyl- 4-(6-phenoxy- pyridin-3-ylamino)- pyrrolo[1,2-b]pyridazine-6- carboxylic acid ethyl ester 3.72 LCMS [M + H]⁺ = 414.0 1129

3-Cyano-5- ethoxymethyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazine-6- carboxylic acid ethyl ester 2.30 LCMS-1 [M + H]⁺ = 457.017 130

2-Acetylamino-N- [3-cyano-5-methyl- 4-(4-phenoxy- phenylamino)-pyrrolo[1,2- b]pyridazin-6-yl]- acetamide 1.70 LCMS-1 [M + H]⁺ = 455.012 131

3-Acetylamino-N- [3-cyano-5-methyl- 4-(4-phenoxy- phenylamino)pyrrolo[1,2- b]pyridazin-6-yl]- propionamide 1.73 LCMS-1 [M + H]⁺ =469.0 12 132

4-Acetylamino-N- [3-cyano-5-methyl- 4-(4-phenoxy- phenylamino)-pyrrolo[1,2- b]pyridazin-6-yl]- butyramide 1.76 LCMS-1 [M + H]⁺ = 483.012 133

4-Acetylamino-N- [3-cyano-5-methyl- 4-(4-phenoxy- phenylamino)-pyrrolo[1,2- b]pyridazin-6-yl]- benzamide 1.85 LCMS-1 [M + H]⁺ = 517.012 134

3-Acetylamino-N- [3-cyano-5-methyl- 4-(4-phenoxy- phenylamino)-pyrrolo[1,2- b]pyridain-6-yl]-benzamide 1.87 LCMS-1 [M + H]⁺ = 517.0 12135

3-Cyano-5- methoxymethyl-4- (4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazine-6- carboxylic acid 3.86 LCMS [M + H]⁺ = 415.0 4, 17 136

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- urea 3.31 LCMS [M + H]⁺ = 399.0 19 137

3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- 1,1-dimethyl-urea 3.38 LCMS [M + H]⁺ = 427.0 19 138

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- ethyl-urea 3.54 LCMS [M + H]⁺ = 427.0 19 139

N-(2-{3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- ureido}-ethyl)- acetamide 3.35 LCMS [M + H]⁺ = 484.019 140

3-Cyano-5- hydroxymethyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazine-6- carboxylic acid 3.66 LCMS [M + H]⁺ = 401.0 4, 16 141

[3-Cyano-5- methoxymethyl-4- (4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid methyl ester 1.99 LCMS-1 [M + H]⁺ =444.0 11, 17 142

3-Cyano-5- methoxymethyl-4- (4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazine-6- carboxylic acid (2- morph- olin-4-yl-ethyl)- amide 1.78LCMS-1 [M + H]⁺ = 527.0 12, 17 143

1-[3-Cyano-5- methoxymethyl-4- (4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-morpholin- 4-yl-ethyl)-urea 1.73 LCMS-1 [M + H]⁺= 542.0 17, 19 144

3- (Methanesulfonyl- amino-methyl)-5- methyl-4-(4- phenoxy-phenylamino)- pyrrolo[1,2- b]pyridazine-6-car- boxylic acid 3.35 LCMS[M + H]⁺ = 467.0 14

EXAMPLE 1456-(1-Hydroxy-1-methyl-ethyl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile(145)

To a solution of compound 3A (124 mg, 0.30 mmol) in THF (5 mL) at 0° C.was slowly added a 3.0 M solution of MeMgBr in ether (0.40 mL, 1.20mmol. The reaction was warmed to room temperature and then heated at 50°C. for 1 h. After cooling to room temperature, the reaction was quenchedwith EtOAc (20 mL) and saturated aqueous NH₄Cl (20 mL) was added. Theresulting two layers were separated and the organic layer washed withbrine, dried over Na₂SO₄ and concentrated to an orange oil. This crudeoil was purified by silica gel flash chromatography (eluted with 14-17%EtOAc/CH₂Cl₂) to give compound 145 as a yellow solid (76 mg, 64%). HPLC:97% at 1.97 min (retention time) (Phenom-Prime S5 C18 column, 4.6×30 mm,eluting with 10-90% aqueous methanol over 2 min containing 0.1% TFA, 5mL/min, monitoring at 220 nm). MS (ES): m/z 399 [M+H]⁺.

EXAMPLE 1466-Hydroxy-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile(146)

To a mixture of H₂O₂ (50% wt in H₂O, 0.0115 mL, 0.20 mmol) and CH₂Cl₂ (2mL) at −5° C. was added BF₃.OEt₂. The reaction was stirred at −5° C. for40 min before a solution of compound 145 (56 mg, 0.14 mmol) in CH₂Cl₂ (3mL) was added. The reaction was kept at −5° C. for 10 min and quenchedwith an aqueous solution of Na₂SO₃ (2 g, 10 mL). The reaction wasdiluted with CH₂Cl₂ and the two layers were separated. The aqueous layerwas extracted with CH₂Cl₂ (2×10 mL). The CH₂Cl₂ layers were combined andconcentrated in vacuo to give a brown oil. This crude oil was purifiedby silica gel flash chromatography (eluted with 10% EtOAc/CH₂Cl₂) togive compound 146 as a yellow solid (32 mg, 64%). HPLC: 90% at 1.89 min(retention time) (Phenom-Prime S5 C18 column, 4.6×30 mm, eluting with10-90% aqueous methanol over 2 min containing 0.1% TFA, 5 mL/min,monitoring at 220 nm). MS (ES): m/z 357 [M+H]⁺.

EXAMPLE 1475-Methyl-6-(2-morpholin-4-yl-ethoxy)-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile(154)

To a solution of compound 146 (8.9 mg, 0.025 mmol) PPh₃ (13.1 mg, 0.05mmol) and 4-(2-hydroxyethyl)-morpholine (6.6 mg, 0.05 mmol) in dry THF(0.3 mL) under N₂ at 0° C. was added DEAD (8.7 mg, 0.05 mmol). Thereaction was stirred at 0° C. for 5 min, warmed to room temperature for2 h, concentrated to dryness, and purified by silica gel flashchromatography (eluted within 1-5% MeOH/CH₂Cl₂) to give compound 147 asa yellow oil (10 mg, 85%). HPLC: 96% at 1.69 min (retention time)(Phenom-Prime SS C18 column, 4.6×30 mm, eluting with 10-90% aqueousmethanol over 2 min containing 0.1% TFA, 5 mL/min, monitoring at 220nm). MS (ES): m/z 470 [M+H]⁺.

EXAMPLE 1485-Cyano-7-oxo-6-(4-phenoxy-phenyl)-6.7-dihydro-9H-8-oxa-2a,3,6-triaza-benzo[cd]azulene-1-carboxylicacid ethyl ester (148)

To a solution of compound 16C (26 mg, 0.061 mmol) and DIPEA (63 mg,0.485 mmol) in CH₂Cl₂ (6 mL) at −50° C. was added triphosgene (30 mg,0.101 mmol). The reaction was slowly warmed up to 10° C. over 1 h,quenched with MeOH (1 mL) concentrated to dryness in vacuo and purifiedby silica gel flash chromatography (eluted with 1-2% EtOAc/CH₂Cl₂) togive compound 148 as a yellow solid (16 mg, 58%). HPLC: 91% at 2.09 min(retention time) (Phenom-Prime S5 C18 column, 4.6×30 mm, eluting with10-90% aqueous methanol over 2 min containing 0.1% TFA, 5 mL/min,monitoring at 220 nm). MS (ES): m/z 455 [M+H]⁺.

EXAMPLE 1495-Azidemethyl-3-cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (149)

To a solution of compound 148 (21 mg, 0.05 mmol) in THF (0.6 mL) wasadded DPPA (22 mg, 0.08 mmol) followed by DBU (9 mg, 0.06 mmol). Thereaction was stirred at room temperature for 4 h; concentrated andpurified by flash chromatography on a silica gel column (0.5-1%EtOAc/CH₂Cl₂) to give compound 149 as a yellow oil (14 mg, 63%). HPLC:99% at 2.16 min (retention time) (PrimeSphere 5u C18-HC column, 4.6×30mm, eluting with 10-90% aqueous methanol over 2 min containing 0.1% TFA,5 mL/min, monitoring at 220 nm). MS (ES): m/z 454 [M+H]⁺.

EXAMPLE 1505-Aminomethyl-3-cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (150)

To a solution of compound 149 (12 mg, 0.026 mmol) in a mixture of 1:2THF: MeOH (3 mL) was added Pd/C (5 mg). The reaction was hydrogenatedunder a hydrogen balloon at room temperature for 30 min and filtered.The filtrate was concentrated to give 8 as a yellow solid (9 mg, 80%).No further purification was required. HPLC: 92% at 1.71 min (retentiontime) (PrimeSphere 5u C18-HC column, 4.6×30 mm, eluting with 10-90%aqueous methanol over 2 min containing 0.1% TFA, 5 mL/min, monitoring at220 nm). MS (ES): m/z 428 [M+H]⁺.

EXAMPLE 1515-Cyano-7-oxo-6-(4-phenoxy-phenyl)-6,7,8,9-tetrahydro-2a,3,6,8-tetraazabenzo[cd]azulene-1-carboxylicacid ethyl ester (151)

To a solution of compound 150 (7 mg, 0.016 mmol) and DIPEA (17 mg, 0.13mmol) in CH₂Cl₂ (1.5 mL) at −70° C. was added triphosegene (9.5 mg,0.032 mmol). The reaction was slowly warmed up to −5° C. over 1 h,quenched with MeOH (0.5 mL), concentrated to dryness and purified bysilica gel flash chromatography (eluted with 6-8% EtOAc/CH₂Cl₂) to give9 as a yellow solid (6 mg, 81%). HPLC: 98% at 1.97 min (retention time)(PrimeSphere 5u (C18-HC column, 4.6×30 mm, eluting with 10-90% aqueousmethanol over 2 min containing 0.1% TFA, 5 mL/min, monitoring at 220nm). MS (ES): m/z 454 [M+H]⁺.

EXAMPLES 152 TO 367

Further compounds of the present invention were prepared by proceduresanalogous to those described. Table 2 provides the name and structure ofrepresentative compounds and their retention times, as well as theExample number of the procedure on which the preparation of the compoundwas based. The chromatography techniques used to determine the retentiontimes of the compounds listed in Table 2 are as follows:

-   -   LC=YMC S5 ODS column, 3.6×50 mm, eluting with 10-90% aqueous        methanol over 2 min containing 0.1% TFA, 5 mL/min, monitoring at        220 nm    -   LC*=YMC S5 ODS column 4.6×50 mm eluting with 10-90% MeOH/H₂O        over 4 minutes containing 0.2% phosphoric acid, 4 mL/min,        monitoring at 220 nm.    -   The molecular mass of the compounds listed in Table 2 were        determined by MS (ES) by the formula m/z.

TABLE 2 Retention Time Min./ Ex. Compound Molecular Proc. No. StructureName Mass of Ex. 152

1-(2-Chloro-ethyl)- 3[3-cyano-5- methyl-4-(4- phenoxy- phenylamino)-pyrrolo[1,2- b]pyridazin-6-yl]- urea 1.74 LC [M + H]⁺ = 416.2 19 153

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-pyrrolidin-1-yl- ethyl)-urea 1.51 LC [M + H]⁺ =496.2 19 154

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- [3-(2-oxo-pyrrolidin- 1-yl)-propyl]-urea 1.67 LC[M + H]⁺ = 524.2 19 155

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- [2-(1H-imidazol-4- yl)-ethyl]-urea 1.51 LC [M + H]⁺= 493.2 19 156

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- [2-(1H-indol-3-yl)- ethyl]-urea 1.86 LC [M + H]⁺ =542.2 19 157

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (3-morpholin-4-yl- propyl)-urea 1.51 LC [M + H]⁺ =526.2 19 158

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-pyridin-2-yl- ethyl)-urea 1.53 LC [M + H]⁺ =504.2 19 159

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-piperidin-1-yl- ethyl)-urea 1.55 LC [M + H]⁺ =510.2 19 160

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- [3-(2-methyl-piper- idin-1-yl)-propyl]-urea 1.57 LC[M + H]⁺ = 538.3 19 161

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-fluoro-ethyl)-urea 1.69 LC [M + H]⁺ = 455.2 19162

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-dimethylamino- ethyl)-urea 1.5 LC [M + H]⁺ =470.2 19 163

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-diethylamino- ethyl)-urea 1.54 LC [M + H]⁺ =498.2 19 164

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-methoxy-ethyl)- urea 1.7 LC [M + H]⁺ = 457.2 19165

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- [2-(2-hydroxy- ethoxy)- ethyl]-urea 1.64 LC [M +H]⁺ = 487.2 19 166

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- propyl-urea 1.78 LC [M + H]⁺ = 441.2 19 167

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (3-dimethylamino- propyl)-urea 1.52 LC [M + H]⁺ =484.2 19 168

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (3-ethoxy-propyl)- urea 1.79 LC [M + H]⁺ = 485.2 19169

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (3-hydroxy-propyl)- urea 1.62 LC [M + H]⁺ = 457.219 170

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (4-hydroxy-butyl)- urea 1.63 LC [M + H]⁺ = 471.3 19171

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- pentyl-urea 1.92 LC [M + H]⁺ = 467.2 19 172

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (5-hydroxy-pentyl)- urea 1.7 LC [M + H]⁺ = 485.2 19173

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (6-hydroxy-hexyl)- urea 1.75 LC [M + H]⁺ = 499.2 19174

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (3-imidazol-1-yl- propyl)-urea 1.53 LC [M + H]⁺ =507.2 19 175

1-(3-Butoxy- propyl)-3-[3-cyano- 5-methyl-4-(4- phenoxy- phenylamino)-pyrrolo[1,2- b]pyridazin-6-yl]- urea 1.91 LC [M + H]⁺ = 513.2 19 176

1-Butyl-3-[3-cyano- 5-methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- urea 1.85 LC [M + H]⁺ = 455.2 19 177

3-{3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- ureido}-propionic acid ethyl ester 1.77 LC [M + H]⁺ =499.2 19 178

6-{3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- ureido}-hexanoic acid methyl ester 1.81 LC [M + H]⁺ =527.2 19 179

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- [3-(4-methyl-piperazin- 1-yl)-propyl]-urea 1.44 LC[M + H]⁺ = 539.2 19 180

1-(2-Cyano-ethyl)-3- [3-cyano-5-methyl- 4-(4-phenoxy- phenylamino)-pyrrolo[1,2- b]pyridazin-6-yl]- urea 1.64 LC [M + H]⁺ = 452.2 19 181

1-{2-[Bis-(2- hydroxy-ethyl)- amino]-ethyl}-3-[3- cyano-5-methyl-4-(4-phenoxy- phenylamino)- pyrrolo[1,2- b]pyridazin-6-yl]- urea 1.46 LC[M + H]⁺ = 530.2 19 182

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (3-methoxy-propyl)- urea 1.71 LC [M + H]⁺ = 471.219 183

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]-pyridazin-6-yl]-3- (2-diisopropyl- aminoethyl)-urea 1.58 LC [M + H]⁺ =526.2 19 184

1-(3-Azepan-1-yl- propyl)-3-[3-cyano- 5-methyl-4-(4- phenoxy-phenylamino)- pyrrolo[1,2- b]pyridazin- 6-yl]-urea 1.59 LC [M + H]⁺ =538.2 19 185

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (3-piperidin-1-yl- propyl)-urea 1.57 LC [M + H]⁺ =524.2 19 186

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-ethoxy-ethyl)- urea 1.76 LC [M + H]⁺ = 471.2 19187

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- [2-(1-methyl-1H-imid- azol-4-yl)-ethyl]- urea 1.52LC [M + H]⁺ = 507.2 19 188

1-(3-Chloro-propyl)- 3-[3-cyano-5- methyl-4-(4- phenoxy- phenylamino)-pyrrolo[1,2- b]pyridazin-6-yl]- urea 1.8 LC [M + H]⁺ = 475.2 19 189

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-pyridin-4-yl-ethyl)- urea 1.53 LC [M + H]⁺ =504.2 19 190

3-{3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- ureido}-propionic acid methyl ester 1.7 LC [M + H]⁺ =485.2 19 191

1-{3-[Bis-(2- hydroxy-ethyl)- amino]-propyl}-3- [3-cyano-5-methyl-4-(4-phenoxy- phenylamino)- pyrrolo[1-2- b]pyridazin-6-yl]- urea 1.48 LC]M + H]⁺ = 544.2 19 192

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1-2-b]pyridazin-6-yl]-3- (4-dimethylamino- butyl)-urea 1.53 LC [M + H]⁺ =498.2 19 193

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (6-dimethylamino- hexyl)-urea 1.6 LC [M + H]⁺ =526.2 19 194

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-diisobutylamino- ethyl)-urea 1.73 LC [M + H]⁺ =552.1 19 195

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-thiophen-2-yl- ethyl)-urea 1.87 LC [M + H]⁺ =509.1 19 196

N-(4-{3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- ureido}-butyl)- acetamide 1.66 LC [M + H]⁺ = 512.2 19197

3-{3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- ureido}- propionamide 1.59 LC [M + H]⁺ = 470.2 19 198

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamnino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (3-propoxy-propyl)- urea 1.85 LC [M + H]⁺ = 499.219 199

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-methyl-butyl)- urea 1.9 LC [M + H]⁺ = 469.2 19200

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- [3-(methyl-phenyl- amino)-propyl]-urea 1.61 LC [M +H]⁺ = 546.2 19 201

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-isopropoxy-ethyl)- urea 1.82 LC [M + H]⁺ = 485.219 202

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-pyridin-3-yl-ethyl)- urea 1.53 LC [M + H]⁺ =504.2 19 203

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2,2,2-trifluoro- ethyl)-urea 1.76 LC [M + H]⁺ =481.1 19 204

4-{3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- ureido}-butyric acid methyl ester 1.71 LC [M + H]⁺ =499.2 19 205

(3-{3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin--yl]- ureido}-propyl)- methyl-carbamic acid tert-butyl ester1.9 LC [M + H]⁺ = 570.3 19 206

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (1-ethyl-pyrrolidin- 2-ylmethyl)-urea 1.55 LC [M +H]⁺ = 510.2 19 207

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (tetrahydro-furan-2- ylmethyl)-urea 1.77 LC [M +H]⁺ = 483.2 19 208

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-hydroxy-2- phenyl-ethyl)-urea 1.79 LC [M + H]⁺ =519.2 19 209

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-hydroxy-propyl)- urea 1.66 LC [M + H]⁺ = 457.219 210

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2,3-dihydroxy- propyl)-urea 1.58 LC [M + H]⁺ =473.2 19 211

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- isobutyl-urea 1.85 LC [M + H]⁺ = 455.2 19 212

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-dimethylamino- propyl)-urea 1.52 LC [M + H]⁺ =484.2 19 213

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- cyclopropylmethyl- urea 1.8 LC [M + H]⁺ = 453.2 19214

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-hydroxy-butyl)- urea 1.73 LC [M + H]⁺ = 471.2 19215

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-hydroxy-propyl)- urea 1.66 LC [M + H]⁺ = 457.219 216

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-hydroxy-propyl)- urea 1.66 LC [M + H]⁺ = 457.219 217

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (tetrahydro-furan-2- ylmethyl)-urea 1.77 LC [M +H]⁺ = 483.2 19 218

4-{3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- ureido}-butyric acid ethyl ester 1.79 LC [M + H]⁺ =513.2 19 219

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (1-ethyl-pyrrolidin- 2-ylmethyl)-urea 1.56 LC [M +H]⁺ = 510.2 19 220

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (tetrahydro-furan-2- ylmethyl)-urea 1.77 LC [M +H]⁺ = 483.2 19 221

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-hydroxy- cyclohexylmethyl)- urea 1.83 LC [M +H]⁺ = 511.2 19 222

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2,2-dimethyl- propyl)-urea 1.9 LC [M + H]⁺ = 469.219 223

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2,3-dihydroxy- propyl)-urea 1.59 LC [M + H]⁺ =473.2 19 224

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2,3-dihydroxy- propyl)-urea 1.59 LC [M + H]⁺ =473.2 19 225

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2,2-dimethyl-[1,3] dioxolan-4-ylmethyl)- urea 1.58LC [M + H]⁺ = 511.2 19 226

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (1-hydroxy- cyclohexylmethyl)- urea 1.84 LC [M +H]⁺ = 511.2 19 227

{3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- ureido}-acetic acid methyl ester 1.66 LC [M + H]⁺ =471.2 19 228

{3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- ureido}-acetic acid ethyl ester 1.72 LC [M + H]⁺ =485.2 19 229

2-{3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- ureido-acetamide 1.58 LC [M + H]⁺ = 456.2 19 230

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (3-hydroxy-2,2- dimethyl-propyl)- urea 1.77 LC [M +H]⁺ = 485.2 19 231

2-{3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- ureido}-N-methyl- acetamide 1.59 LC [M + H]⁺ = 470.219 232

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- furan-2-ylmethyl- urea 1.79 LC [M + H]⁺ = 479.2 19233

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- naphthalen-1- ylmethyl-urea 1.94 LC [M + H]⁺ =539.1 19 234

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- thiophen-2- ylmethyl- urea 1.83 LC [M + H]⁺ = 495.219 235

1-Benzo[1,3]dioxol- 5-ylmethyl-3-[3- cyano-5-methyl-4- (4-phenoxy-phenylamino)- pyrrolo[1,2- b]pyridazin-6-yl]- urea 1.84 LC [M + H]⁺ =533.1 19 236

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- pyridin-2-ylmethyl- urea 1.53 LC [M + H]⁺ = 490.219 237

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- pyridin-3-ylmethyl- urea 1.52 LC [M + H]⁺ = 490.219 238

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- pyridin-4-ylmethyl- urea 1.52 LC [M + H]⁺ = 490.219 239

1-Benzyl-3-[3- cyano-5-methyl-4- (4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- urea 1.85 LC [M + H]⁺ = 489.2 19 240

1-(4-Amino-2- methyl-pyrimidin-5- ylmethyl)-3-[3- cyano-5-methyl-4-(4-phenoxy- phenylamino)- pyrrolo[1,2- b]pyridazin-6-yl]- urea 1.53 LC[M + H]⁺ = 520.1 19 241

6-Methoxy-5- methyl-4-[methyl- (4-phenoxy-phenyl)- amino]-pyrrolo[1,2-b]pyridazine-3- carbonitrile 2.17 LC [M + H]⁺ = 385.2 154 242

1-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (2-hydroxy-ethyl)- urea 1.77 LC [M + H]⁺ = 443.2 19243

3-Cyano-5-(2- methoxy- ethoxymethyl)-4-(4- phenoxy- phenylamino)-pyrrolo[1,2- b]pyridazine-6- carboxylic acid ethyl ester 2.19 LC [M +H]⁺ = 487.2 17B 244

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- morpholin- 4-yl-ethyl ester 1.50 LC[M + H]⁺ = 513.2 11A 245

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- methoxy- ethyl ester 1.71 LC [M +H]⁺ = 458.2 11A 246

3-Cyano-4-(2,4- dichloro- phenylamino)-5- methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid ethyl ester 4.39 LC* [M + H]⁺ = 390.0 1E247

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- piperidin-1-yl- propionamide 1.52 LC [M + H]⁺ =495.2 12 248

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridiazin-6-yl]- carbamic acid 2- dimethyl amino-ethyl ester 1.55 LC[M + H]⁺ = 471.2 11A 249

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- diethyl- amino-ethyl ester 1.52 LC[M + H]⁺ = 499.2 11A 250

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- phenoxy- ethyl ester 1.90 LC [M +H]⁺ = 520.1 11A 251

Acetic acid 2-[3- cyano-5-methyl-4- (4-phenoxy- phenylamino)-pyrrolo[1,2- b]pyridazin-6- ylcarbamoyloxy]- ethyl ester 1.72 LC [M +H]⁺ = 486.2 11A 252

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- isopropoxy-ethyl ester 1.74 LC [M +H]⁺ = 486.4 11A 253

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- ethoxy-ethyl ester 1.77 LC [M + H]⁺= 472.2 11A 254

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2-(3- methoxy-phenyl)- ethyl ester 1.92LC [M + H]⁺ = 534.2 11A 255

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 3- methoxy- butyl ester 1.81 LC [M +H]⁺ = 486.2 11A 256

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 3- dimethylamino- propyl ester 1.56 LC[M + H]⁺ = 485.2 11A 257

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 3- diethylamino-propyl ester 1.58 LC[M + H]⁺ = 513.2 11A 258

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 3- (3,4-dimethoxy- phenyl)-propyl ester1.90 LC [M + H]⁺ = 578.2 11A 259

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 3-(4- methoxy-phenyl)- propyl ester1.96 LC [M + H]⁺ = 548.2 11A 260

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2-(1- methyl-pyrrolidin-2- yl)-ethylester 1.59 LC [M + H]⁺ = 511.2 11A 261

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- pyrrolidin-1-yl-ethyl ester 1.56 LC[M + H]⁺ = 497.2 11A 262

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid [1,3]dioxolan-4- ylmethyl ester 1.70 LC[M + H]⁺ = 486.2 11A 263

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid tetrahydro- furan-3-yl ester 1.72 LC[M + H]⁺ = 470.2 11A 264

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- thiophen- 2-yl-ethyl ester 1.90 LC[M + H]⁺ = 510.1 11A 265

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- (1,3-dioxo-1,3- dihydro-isoindol-2-yl)-ethyl ester 1.80 LC [M + H]⁺ = 573.2 11A 266

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- pyridin-2-yl-ethyl ester 1.57 LC[M + H]⁺ = 505.2 11A 267

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 3- pyridin-3-yl-propyl ester 1.61 LC[M + H]⁺ = 519.2 11A 268

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 1- methyl-piperidin-2- ylmethyl ester1.60 LC [M + H]⁺ = 511.2 11A 269

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 1- methyl-piperidin-3- ylmethyl ester1.60 LC [M + H]⁺ = 511.2 11A 270

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- piperidin-1-yl-ethyl ester 1.54 LC[M + H]⁺ = 511.2 11A 271

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- diisopropylamino- ethyl ester 1.59LC [M + H]⁺ = 527.2 11A 272

3-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6- ylcarbamoyloxy]- 2,2-dimethyl- propionic acid methylester 1.83 LC [M + H]⁺ = 514.2 11A 273

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2-(2- methyl-5-nitro-imidazol-1-yl)-ethyl ester 1.70 LC [M + H]⁺ = 553.2 11A 274

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- thiophen-3-yl-ethyl ester 1.95 LC[M + H]⁺ = 510.2 11A 275

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2-[(2- dimethylamino- ethyl)-methyl-amino]-ethyl ester 1.43 LC [M + H]⁺ = 528.2 11A 276

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 3-(6- methyl-pyridin-2- yl)-propylester 1.61 LC [M + H]⁺ = 533.2 11A 277

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2-(2- oxo-pyrrolidin-1-yl)- ethyl ester1.68 LC [M + H]⁺ = 511.2 11A 278

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- (methylphenyl- amino)-ethyl ester1.72 LC [M + H]⁺ = 533.2 11A 279

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- azepan-1-yl-ethyl ester 1.56 LC [M +H]⁺ = 525.2 11A 280

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- dimethylamino-2- methyl-propyl ester1.57 LC [M + H]⁺ = 499.2 11A 281

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 1- methyl-2-piperidin- 1-yl-ethyl ester1.58 LC [M + H]⁺ = 525.2 11A 282

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 3- piperidin-1-yl-propyl ester 1.60 LC[M + H]⁺ = 525.2 11A 283

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 5-oxo- tetrahydro-furan-2- ylmethylester 1.70 LC [M + H]⁺ = 498.2 11A 284

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 3- pyridin-2-yl-propyl ester 1.60 LC[M + H]⁺ = 519.2 11A 285

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 3-(2- oxo-pyrrolidin-1-yl)- propylester 1.72 LC [M + H]⁺ = 525.2 11A 286

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- propionylamino- ethyl ester 1.68 LC[M + H]⁺ = 499.2 11A 287

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2-(2- dimethylamino- ethoxy)-ethylester 1.58 LC [M + H]⁺ = 515.2 11A 288

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- [(pyridine-4- carbonyl)-amino]-ethyl ester 1.58 LC [M + H]⁺ = 548.2 11A 289

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- (2,5-dioxo- pyrrolidin-1-yl)- ethylester 1.64 LC [M + H]⁺ = 523.2 11A 290

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl] carbamic acid 2- pyridin-4-yl-ethyl ester 1.57 LC [M +H]⁺ = 505.2 11A 291

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 5- hydroxymethyl-3H-imidazol-4-ylmethyl ester 1.49 LC [M + H]⁺ = 510.2 11A 292

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- imidazol-1-yl-ethyl ester 1.55 LC[M + H]⁺ = 494.2 11A 293

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 2- (isopropyl-methyl- amino)-ethylester 1.58 LC [M + H]⁺ = 499.2 11A 294

3-Cyano-4-[4-(2- methoxy-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid ethyl ester 1.86 LC [M + H]⁺ = 443.2 1E295

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- methoxy- propionamide 1.64 LC [M + H]⁺ = 442.2 12296

4-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6- ylcarbamoyl]-butyric acid methyl ester 1.69 LC [M + H]⁺ =484.2 12 297

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- hydroxy- propionamide 1.55 LC [M + H]⁺ = 428.2 12298

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- ethoxy- propionamide 1.71 LC [M + H]⁺ = 456.2 12299

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- (1H-indol-3-yl)- propionamide 1.8 LC [M + H]⁺ =527.2 12 300

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- pyridin-3-yl- propionamide 1.49 LC [M + H]⁺ = 489.212 301

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- diethylamino- propionamide 1.54 LC [M + H]⁺ = 483.312 302

1-Methyl-1,2,5,6- tetrahydro-pyridine- 3-carboxylic acid [3-cyano-5-methyl-4- (4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- amide 1.51 LC [M + H]⁺ = 479.3 12 303

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- butyramide 1.73 LC [M + H]⁺ = 426.2 12 304

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-4- dimethylamino- butyramide 1.55 LC [M + H]⁺ = 469.312 305

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-2- pyridin-2-yl- acetamide 1.5 LC [M + H]⁺ = 475.3 12306

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino) pyrrolo[1,2-b]pyridazin-6-yl]-2- pyridin-3-yl- acetamide 1.48 LC [M + H]⁺ = 475.3 12307

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-2- pyridin-4-yl- acetamide 1.47 LC [M + H]⁺ = 475.3 12308

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-2- thiophen-2-yl- acetamide 1.76 LC [M + H]⁺ = 480.212 309

Pyridine-2- carboxylic acid [3- cyano-5-methyl-4- (4-phenoxy-phenylamino)- pyrrolo[1,2- b]pyridazin-6-yl]- amide 1.87 LC [M + H]⁺ =461.2 12 310

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- nicotinamide 1.59 LC [M + H]⁺ = 461.2 12 311

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- isonicotinamide 1.57 LC [M + H]⁺ = 461.2 12 312

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-2- dimethylamino- acetamide 1.5 LC [M + H]⁺ = 441.2 12313

2-Cyano-N-[3- cyano-5-methyl-4- (4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- acetamide 1.64 LC [M + H]⁺ = 423.2 12 314

2-tert-Butyl-5- methyl-2H-pyrazole 3-carboxylic acid [3-cyano-5-methyl-4- (4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- amide 1.85 LC [M + H]⁺ = 520.2 12 315

5-Methyl-pyrazine- 2-carboxylic acid [3- cyano-5-methyl-4- (4-phenoxy-phenylamino)- pyrrolo[1,2-b]pyrid- azin-6-yl]-amide 1.83 LC [M + H]⁺ =476.3 12 316

1,5-Dimethyl-1H- pyrazole-3- carboxylic acid [3- cyano-5-methyl-4-(4-phenoxy- phenylamino)- pyrrolo[1,2- b]pyridazin-6-yl]- amide 1.78 LC[M + H]⁺ = 478.3 12 317

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-2- fluoro-3-pyridin-3- yl-acrylamide 1.6 LC [M + H]⁺ =505.2 12 318

4-Methyl- [1,2,3]thiadiazole-5- carboxylic acid [3- cyano-5-methyl-4-(4-phenoxy- phenylamino)- pyrrolo[1, 2-b]pyridazin-6-yl]- amide 1.74 LC[M + H]⁺ = 482.2 12 319

1-Methyl-1H- imidazole-2- carboxylic acid [3- cyano-5-methyl-4-(4-phenoxy- phenylamino)- pyrrolo[1,2- b]pyridazin-6-yl]- amide 1.7 LC[M + H]⁺ = 464.3 12 320

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-3- dimethylamino- benzamide 1.62 LC [M + H]⁺ = 503.312 321

Isoxazole-5- carboxylic acid [3- cyano-5-methyl-4- (4-phenoxy-phenylamino)- pyrrolo[1,2- b]pyridazin-6- yl]-amide 1.67 LC [M + H]⁺ =451.2 12 322

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-6- methyl-nicotinamide 1.52 LC [M + H]⁺ = 475.3 12 323

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-2- methyl-nicotinamide 1.5 LC [M + H]⁺ = 475.3 12 324

1-Methyl-1H- pyrrole-2-carboxylic acid [3-cyano-5- methyl-4-(4- phenoxy-phenylamino)- pyrrolo[1,2-b] pyridazin-6-yl]- amide 1.76 LC [M + H]⁺ =463.3 12 325

N-[3-Cyano-5- methyl-4-(4- phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]-4- methoxy-butyramide 1.67 LC [M + H]⁺ = 456.2 12 326

{3-Cyano-4-[4-(2- methoxy-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}- carbamic acid 2-methoxy-ethyl ester 1.64 LC [M + H]⁺= 488.4 11A 327

{3-Cyano-4-[4-(2- methoxy-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}- carbamic acid 2-morpholin-4-yl- ethyl ester 1.42 LC[M + H]⁺ = 543.4 11A 328

1-{3-Cyano-4-[4-(2- methoxy-phenoxy)- phenylamino]-5-methyl-pyrrolo[1,2- b]pyridazin-6-yl}-3- (2-methoxy-ethyl)- urea 1.39 LC[M + H]⁺ = 542.4 19 329

1-{3-Cyano-4-[4-(2- methoxy-phenyl)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- (2-morpholin-4-yl- ethyl)-urea 1.58 LC [M + H]⁺ =487.2 19 330

{3-Cyano-4-[4-(2- methoxy-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}- carbamic acid benzyl ester 1.83 LC [M + H]⁺ = 520.211A 331

3-Cyano-4-[4-(2- methoxy-phenoxy)- phenylamino]-2- methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid 1.66 LC [M + H]⁺ = 415.2 9 332

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid furan- 2-ylmethyl ester 1.80 LC [M +H]⁺ = 480.2 11A 333

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid oxiranylmethyl ester 1.67 LC [M + H]⁺ =456.3 11A 334

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid furan- 3-ylmethyl ester 1.84 LC [M +H]⁺ = 480.3 11A 335

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid tetrahydro-furan-2- ylmethyl ester 1.76LC [M + H]⁺ = 484.3 11A 336

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid 3- methyl-oxetan-3- ylmethyl ester 1.75LC [M + H]⁺ = 484.2 11A 337

[3-Cyano-5-methyl- 4-(4-phenoxy- phenylamino)- pyrrolo[1,2-b]pyridazin-6-yl]- carbamic acid tetrahydro-furan-3- ylmethyl ester 1.75LC [M + H]⁺ = 484.3 11A 338

3-Cyano-4-[4-(4- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid ethyl ester 1.93 LC [M + H]⁺ = 431.2 1E339

3-Cyano-4-[4-(3- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid ethyl ester 1.92 LC [M + H]⁺ = 431.2 1E340

3-Cyano-4-[4-(2- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid ethyl ester 1.86 LC [M + H]⁺ = 431.2 1E341

3-Cyano-4-[4-(3- methoxy-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid ethyl ester 1.96 LC [M + H]⁺ = 443.3 1E342

3-Cyano-4-[4-(4- methoxy-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid ethyl ester 1.89 LC [M + H]⁺ = 443.2 1E343

3-Cyano-4-[4-(2- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid 1.65 LC [M + H]⁺ = 403.3 9 344

3-Cyano-4-[4-(3- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid 1.70 LC [M + H]⁺ = 403.3 9 345

3-Cyano-4-[4-(4- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid 1.69 LC [M + H]⁺ = 403.3 9 346

3-Cyano-4-[4-(3- methoxy-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid 1.74 LC [M + H]⁺ = 415.2 9 347

3-Cyano-4-[4-(4- methoxy-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridiazine-6- carboxylic acid 1.66 LC [M + H]⁺ = 415.2 9 348

1-{3-Cyano-4-[4-(2- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- (2-morpholin-4-yl- ethyl)-urea 1.46 LC [M + H]⁺ =530.3 19 349

1-{3-Cyano-4-[4-(3- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- (2-morpholin-4-yl- ethyl)-urea 1.53 LC [M + H]⁺ =530.3 19 350

1-{3-Cyano-4-[4-(4- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- (2-morpholin-4-yl- ethyl)-urea 1.50 LC [M + H]⁺ =530.3 19 351

1-{3-Cyano-4-[4-(3- methoxy-phenoxy)- phenylamino]-5-methyl-pyrrolo[1,2- b]pyridazin-6-yl}-3- (2-morpholin-4-yl- ethyl)-urea1.51 LC [M + H]⁺ = 542.4 19 352

1-{3-Cyano-4-[4-(4- methoxy-phenoxy)- phenylamino]-5-methyl-pyrrolo[1,2- b]pyridazin-6-yl}-3- (2-morpholin-4-yl- ethyl)-urea1.49 LC [M + H]⁺ = 542.4 19 353

1-{3-Cyano-4-[4-(2- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- (2-methoxy-ethyl)- urea 1.64 LC [M + H]⁺ = 475.3 19354

1-{3-Cyano-4-[4-(3- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- (2-methoxy-ethyl)- urea 1.69 LC [M + H]⁺ = 475.3 19355

1-{3-Cyano-4-[4-(4- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- (2-methoxy-ethyl)- urea 1.68 LC [M + H]⁺ = 475.3 19356

1-{3-Cyano-4-[4-(3- methoxy-phenoxy)- phenylamino]-5-methyl-pyrrolo[1,2- b]pyridazin-6-yl}-3- (2-methoxy-ethyl)- urea 1.68 LC[M + H]⁺ = 487.3 19 357

1-{3-Cyano-4-[4-(4- methoxy-phenoxy)- phenylamino]-5-methyl-pyrrolo[1,2- b]pyridazin-6-yl}-3- (2-methoxy-ethyl)- urea 1.64 LC[M + H]⁺ = 487.4 19 358

{3-Cyano-4-[4-(2- fluoro-phenoxy)- phenylanmino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}- carbamic acid 2-morpholin-4-yl- ethyl ester 1.47 LC[M + H]⁺ = 531.3 11A 359

{3-Cyano-4-[4-(3- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}- carbamic acid 2-morpholin-4-yl- ethyl ester 1.53 LC[M + H]⁺ = 531.3 11A 360

{3-Cyano-4-[4-(4- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}- carbamic acid 2-morpholin-4-yl- ethyl ester 1.51 LC[M + H]⁺ = 531.3 11A 361

{3-Cyano-4-[4-(3- methoxy-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}- carbamic acid 2- morpholin-4-yl-ethyl- ester 1.52 CL[M + H]⁺ = 543.4 11A 362

{3-Cyano-4-[4-(4- methoxy-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}- carbamic acid 2- morpholin-4-yl-ethyl- ester 1.48 LC[M + H]⁺ = 543.4 11A 363

{3-Cyano-4-[4-(2- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}- carbamic acid 2-methoxy-ethyl ester 1.68 LC [M + H]⁺= 476.3 11A 364

{3-Cyano-4-[4-(3- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}- carbamic acid 2-methoxy-ethyl ester 1.68 LC [M + H]⁺= 476.3 11A 365

{3-Cyano-4-[4-(4- fluoro-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}- carbamic acid 2-methoxy-ethyl ester 1.72 LC [M + H]⁺= 476.3 11A 366

{3-Cyano-4-[4-(3- methoxy-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}- carbamic acid 2- methoxy-ethyl ester 1.78 LC [M + H]⁺= 488.3 11A 367

{3-Cyano-4-[4-(4- methoxy-phenoxy)- phenylamino]-5- methyl-pyrrolo[1,2-b]pyridazin-6-yl}- carbamic acid 2- methoxy-ethyl ester 1.68 LC [M + H]⁺= 488.3 11A

EXAMPLE 368 Preparation of3-Cyano-4-[4-(cyano-phenyl-methyl)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester (368)

4-Chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acidethyl ester (5 mg, 0.019 mmol) and (4-Amino-phenol)-phenyl-acetonitrile(8 mg, 0.016 mmol) in DMF (0.5 ml) were heated at 110° C. for 3 hrs. Thereaction mixture was purified by silica gel flash chromatography toisolate3-cyano-4-[4-cyano-phenyl-methyl)phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester 368 as yellow film (4.3 mg, 52%). [M+H]⁺=436.1.

EXAMPLE 369 Preparation of2-[3-Cyano-6-ethoxycarbonyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-5-ylmethyl]-malonicacid diethyl ester (369)

369B—Synthesis of1-(4-Chloro-3-cyano-6-ethoxycarbonyl-pyrrolo[1,2-b]pyridazin-5-ylmethyl)-malonicacid diethyl ester)

LDA (0.084 mmol, 2.0 M solution in heptane/THF) was added to diethylmalonate (0.096 mmol, 15.3 mg) in THF (0.5 ml) at 0° C. After 5 min,5-bromomethyl-4-chloro-3-cyano-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester 369A (0.048 mmol, 16.2 mg) in THF (0.5 ml) was added.After 10 min, the reaction mixture was placed at RT and stirred for 1hr, quenched with pH 7 phosphate buffer (5 ml) and extracted withdichloromethane (3×5 ml), dried over Na₂SO₄, concentrated and purifiedby silica gel flash chromatography to isolate 369B as a yellow film (6.5mg, 31%). [M+H]⁺=443.

(2) Preparation of2-[3-Cyano-6-ethoxycarbonyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-5-ylmethyl]-malonicacid diethyl ester

A solution of2-(4-Chloro-3-cyano-6-ethoxycarbonyl-pyrrolo[1,2-b]pyridazin-5-ylmethyl)-malonicacid diethyl ester 369B (6.5 mg, 0.015 mmol) and 4-phenoxyphenylamine(4.2 mg, 0.023 mmol) in DMF (0.5 ml) was heated at 110° C. for 4 hrs.The reaction mixture was purified by silica gel flash chromatography toisolate 369 as a yellow film (1.7 mg, 20%). [M+H]⁺32 571.

EXAMPLE 370 Preparation of5-Methyl-4-(4-phenoxy-phenylamino)-6-phenylamino-pyrrolo-[1,2-b]pyridazine-3-carbonitrile(370)

6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (10.3 mg, 0.026 mmol), benzeneboronic acid (4.7 mg, 0.039mmol), Cu(OAc)₂ (0.039 mmol, 7 mg) and TEA (0.13 mmol, 13 mg) indichloromethane (1 ml) were stirred at RT for 16 hrs. The reactionmixture was purified by silica gel flash chromatography to isolate 370as a yellow film (1.4 mg, 15%). [M+H]⁺=432.1.

EXAMPLE 371 Preparation of3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid (2-amino-phenyl)-amide (371)

3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboyxlicacid (40 mg, 0.1 mmol), phenylenediamine (16 mg, 0.15 mmol), PyBOP (78mg, 0.15 mmol) and DIEA (19.4 mg, 0.15 mmol) in 1,2-dichloroethane (1.5ml) were stirred at RT for 48 hrs. The reaction mixture was concentratedand purified by silica gel flash chromatography to isolate 371 as ayellow film (17.6 mg, 37%). [M+H]⁺=475.11.

EXAMPLE 372 Preparation of{3-cyano-5-methyl-4-[(4-phenoxyphenyl)amino](7a-hydropyrrolo[1,2-e]pyridazin-6-yl)}-N-[2-({3-cyano-5-methyl-4-[(4-phenoxyphenyl)amino](7a-hydropyrrole[1,2-e]pyridazin-6-yl)}carbonylamino)phenyl]carboxamide(372)

Compound 372 was the second product isolated from example 371 as ayellow film (10.6 mg, 12%). [M+H]⁺=841.

EXAMPLE 373 Preparation of6-(1H-Benzoimidazol-2-yl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile(373)

3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid (2-amino-phenyl)-amide 371 (4 mg, 0.008 mmol) and a small pinch of10-camphorsulfonic acid was heated in toluene (1.0 ml) at 110° C. for 5hrs. The reaction mixture was purified by silica gel flashchromatography to isolate 373 as yellow film (1.9 mg, 33%).[M+H]⁺=436.1.

EXAMPLE 374 Preparation ofN-[3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-yl]-2-fluoro-benzamide(374)

6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (8 mg, 0.02 mmol), 2-fluorobenzoic acid (4.2 mg, 0.03mmol), PyBOP (16 mg, 0.03 mmol) and DIEA (6.5 mg, 0.05 mmol) in1,2-dichloroethane (0.5 ml) were stirred at RT for 16 hrs. The reactionmixture was concentrated and purified by silica gel flash chromatographyto isolate 374 as a white solid (4 mg, 42%). [M+H]⁺=478.

EXAMPLES 375 Preparation of5-Methyl-6-(2-methyl-4-oxo-4H-quinazolin-3-yl)-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile(375)

6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (10.4 mg, 0.027 mmol), 2-acetylamino benzoic acid (7 mg,0.04 mmol), PyBOP (21 mg, 0.04 mmol) and DIEA (8.6 mg, 0.067 mmol) in1.2-dichloroethane (0.5 ml) were stirred at RT for 16 hrs. The reactionmixture was concentrated and purified by silica gel flash chromatographyto isolate 375 as a yellow film (5.8 mg, 42%). [M+H]⁺=498.

EXAMPLE 376 Preparation of6-Benzylamino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo-[1,2-b]pyridazine-3-carbonitrile(376)

6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (10 mg, 0.026 mmol), benzaldehyde (2.8 mg, 0.026 mmol) andacetic acid (0.5 ml) in 1,2-dichloroethane (1.0 ml) were stirred at RT.After 20 minutes, NaBH(OAc)₃ was added and the reaction mixture wasstirred for additional 15 minutes, quenched with saturated NH₄OH (4.0ml), extracted with dichloromethane (3×3 ml), dried over Na₂SO₄,concentrated and purified by silica gel flash chromatography to isolate376 as a yellow film (1.3 mg, 11%). [M+H]⁺=446.2.

EXAMPLE 377 Preparation ofN-[3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-yl]-benzenesulfonamide(377)

To6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (8.2 mg, 0.021 mmol) and DIEA (5.4 mg, 0.042 mmol) indichloromethane (1.0 ml) was added benzenesulfonyl chloride (3.7 mg,0.021 mmol) at RT for 2 hrs. The reaction mixture was quenched with pH 7phosphate buffer (2 ml), dried over Na₂SO₄, concentrated and purified bysilica gel flash chromatography to isolate 377 as a yellow film (3 mg,29%). [M+H]⁺=496.1.

EXAMPLE 378 Preparation of6-[bis(phenylsulfonyl)amino]-5-methyl-4-[(4-phenoxyphenyl)amino]-7a-hydropyrrolo[1,2-e]pyridazine-3-carbonitrile(378)

To6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (7 mg, 0.018 mmol) and DIEA (5.8 mg, 0.045 mmol) in1,2-dichloromethane (1.0 ml) was added benzenesulfonyl chloride (3.9 mg,0.022 mmol) at RT for 12 hrs. The reaction mixture was quenched with pH7 phosphate buffer (2 ml), dried over Na₂SO₄, concentrated and purifiedby silica gel flash chromatography to isolate 378 as a yellow film (3.1mg, 27%). [M+H]⁺=636.05.

EXAMPLES 379 Preparation of6-(Benzothiazol-2-ylamino)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile(379)

6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (9.5 mg, 0.024 mmol) and 2-chlorobenzothiazole (4.4 mg,0.026 mmol) in DMF (0.1 ml) were stirred at 100° C. for 12 hrs. Thereaction mixture was concentrated and purified by silica gel flashchromatography to isolate 379 as a yellow film (3.3 mg, 28%).[M+H]⁺489.14

EXAMPLE 380 Preparation of{4-[4-(6-Chloro-pyridazin-3-yloxy)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2 morpholin-4-yl-ethyl ester

380B-Synthesis of4-(4-Benzyloxy-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid

To4-(4-Benzyloxy-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester 380A (3.4 mmol, 1.4 g) in methanol (15 ml) was added1N sodium hydroxide (15 ml), and the reaction mixture was heated a 65°C. for 30 hrs. The methanol was removed under vacuum, and the remainingmixture was dissolved in 1N HCl (200 ml), extracted with ethyl acetate(2×300 mL), dried over sodium sulfate. The organic layer wasconcentrated to afford 380B as a yellow solid (750 mg, 56%), which wastaken to next step without further purification, [M+H]⁺=399.14.

380C—Synthesis of[4-(4-Benzyloxy-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-carbamicacid 2-morpholin-4-yl-ethyl ester

[4-(4-Benzyloxy-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6yl]-carbamicacid 2-morpholin-4-yl-ethyl ester 380B (646 mg, 1.62 mmol), DPPA (535mg, 1.95 mmol), and triethylamine (246 mg, 2.43 mmol) in dioxane (10 ml)were stirred at RT. After 20 hrs, 4-(2-hydroxyethyl)morpholine (425 mg,3.24 mmol) was added, and the reaction mixture was heated at 80° C. for5 hrs. The reaction mixture was diluted with aqueous NH₄OH (75 ml) andextracted with ethyl acetate (4×200 ml). The combined organic layerswere dried over sodium sulfate, concentrated and purified by silica gelflash chromatography to afford 380C as a yellow solid (675 mg, 79%).[M+H]⁺=527.13.

380D—Synthesis of[3-Cyano-4-(4-hydroxy-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-carbamicacid 2-morpholin-4-yl-ethyl ester

[4-(4-Benzyloxy-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-carbamicacid 2-morpholin-4-yl-ethyl ester 380C (0.79 mmol, 420 mg) and 10% Pd(C)(180 mg) in DMF (10 ml) were stirred under H₂ gas (1 atm) for 24 hours.The reaction mixture was filtered to afford 380D as a yellow solid (320mg, 92%). [M+H]⁺=437.21.

[3-Cyano-4-(4-hydroxy-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-carbamicacid 2-morpholin-4-yl-ethyl ester 380D (0.037 mmol, 16 mg), 6.5 mg3,6-dichloropyridazine (0.044 mmol, 6.5 mg), and potassium carbonate(0.044 mmol, 6.1 mg) were stirred at 80° C. for 48 hrs. The reactionmixture was concentrated and purified using prep HPLC to obtain 380 as ayellow film (0.52 mg, 3%). [M+H]⁺=549.2

EXAMPLE 381 Preparation of{3-Cyano-5-methyl-4-[4-(1-phenyl-1H-tetrazol-5-yloxy)-phenylamino]-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester

Compound 381 (12.7 mg, 60%) was prepared using the same procedure usedto prepared compound 380 from compound 380D in example 380. [M+H]⁺=581.1.

EXAMPLE 382 Preparation of{3-Cyano-5-methyl-4-[4-(2-nitro-phenoxy)-phenylamino]-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester

Compound 382 (15 mg, 36%) was prepared using the same procedure used toprepare compound 380 from compound 380D in example 380. [M+H]⁺=558.07

EXAMPLE 383 Preparation of{4-[4-(2-Amino-phenoxy)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester

{3-Cyano-5-methyl-4-[4-(2-nitro-phenoxy)-phenylamino]-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester 382 (0.025 mmol, 14 mg) and 10% Pd oncarbon (15 mg) in ethanol/DMF (2:1, 3 ml) were stirred at RT for 2.5 hrsunder atmosphere of H₂ gas (1 atm). The reaction mixture was filteredand concentrated to obtain compound 383 as a brown/orange oil (13 mg,100%). [M+H]⁺=528.14.

EXAMPLE 384 Preparation of{4-[4-(2-Acetylamino-phenoxy)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester

{4-[4-(2-Amino-phenoxy)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester 383 (0.013 mmol, 7 mg, aceticanhydride (0.44 mmol, 45 mg), and triethylamine (0.28 mmol, 28 mg) indichloromethane (1 ml) were stirred at RT for 30 hours. The reactionmixture was diluted in saturated sodium bicarbonate (20 ml), extractedwith dichloromethane (70 ml), dried over sodium sulfate, and purified bysilica gel flash chromatography (5% MeOH/CHCl₃) to isolate compound 384as a yellow film (1.9 mg, 27%). [M+H]⁺=570.14.

EXAMPLE 385 Preparation of5-Methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

3-Cyano-5-methyl-4-[4-(1-vinyl-propenyloxy)-phenylamino]-pyrrolo[1,2-b]pyridazine-6-carboxylicacid 385A (32 mg, 0.083 mmol), and copper oxide (7 mg, 0.049 mmol) indi(ethylene glycol) methyl ether (2 ml) were heated at 185° C. for 21hrs. The reaction mixture was diluted in NH₄OH (aq) (25 ml), extractedwith methylene chloride (75 ml), dried over sodium sulfate, and purifiedby silica gel flash chromatography (20% ethyl acetate in hexanes) toafford compound 385 as a yellow oil (1.6 mg, 6%). [M+H]⁺=476.3.

EXAMPLE 386 Preparation of[4-(4-Bromo-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-carbamicacid 2-morpholin-4-yl-ethyl ester

Compound 386 was prepared from compound 386A using the same procedureused to prepare compound 380C from compound 380B (example 442). Compound386 was isolated as a yellow solid (1.345 g, 51%). [M+H]⁺=500.9.

EXAMPLE 387 Preparation of{3-Cyano-4-[4-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-7-yloxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester

387A—Synthesis of[4-(4-Dihydroxyboron-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-carbamicacid 2-morpholin-4-yl-ethyl ester

Compound 386 (48.5 mg, 0.097 mmol), bis(pinacolato)diboron (28 mg, 0.11mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)•CH₂Cl₂ (8 mg, 0.0097 mg) and potassium acetate (29 mg, 0.29 mmol)in degassed DMSO (1.0 ml) was heated at 80° C. for 12 hrs. Additionalbis(pinacolato)diboron (28 mg, 0.11 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II)•CH₂Cl₂ (8mg, 0.0097 mg) and potassium acetate (29 mg, 0.29 mmol) were added, andthe reaction was heated at 80° C. for 4 hours. The reaction mixture wasdiluted with water (10 ml) and extracted with dichloromethane (2×10 ml).The pooled organic phase was washed with saturated NaCl (10 ml), driedover Na₂SO₄, and concentrated. The reaction mixture was dissolved inacetone/water (1:1, 1.5 ml) and treated with NaIO₄ (0.29 mmol, 63 mg)and NH₄OAc (0.29 mmol, 23 mg). After 7 hrs, additional NaIO₄ (0.29 mmol,63 mg) and NH₄OAc (0.29 mmol, 23 mg) were added. After 2 hrs, thereaction mixture was diluted with water (15 ml) and extracted with 10%isopropanol/dichloromethane (3×10 ml), dried over Na₂SO₄, concentrated,and purified using reverse phase HPLC to isolate 387A as a yellow film(4.8 mg, 11% for two steps). [M+H]⁺=465.17

387—Synthesis of{3-Cyano-4-[4-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-7-yloxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester

Compound 387A (0.010 mmol, 6.0 mg),7-Hydroxy-2,2-dimethyl-benzofuran-3-one (0.015 mmol, 3.0 mg), copper(II) acetate (0.015 mmol, 3.0 mg), and triethylamine (10 mg) indichloromethane (1.0 ml) were stirred at RT. After 24 hrs, the reactionmixture was concentrated, and purified using reverse phase HPLC toisolate 387 as a yellow film (0.42 mg, 7%). [M+H]⁺=597.1

EXAMPLE 388

4-(4-{2-[1-(tert-Butoxycarbonylmethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester 388A—Preparation of 2-(4-nitro-phenoxy)-phenol

Anhydrous DMA (50 ml) was added to t-BuOK (5.46 g, 48.7 mmol) andcatechol (5.00 g, 45.4 mmol) at 0° C. under argon, the mixture washeated to 120° C. over 10 min. A solution of 1-fluoro-4-nitro-benzene(6.40 g, 45.4 mmol) in anhydrous DMA (10 ml) was added dropwise over 20min. The reaction mixture was then stirred at 130° C. for 1.5 h, cooled,and poured into 1N HCl (200 ml), extracted with EtOAc (2×50 ml). Thecombined extract was washed H₂O (3×150 ml), brine (150 ml), dried withNa₂SO₄, concentrated and purified by silica gel flash columnchromatography to give desired product 388A (5.56 g, 53%) as a faintlyyellow solid (0%-1% ethyl acetate-CH₂Cl₂).

388B—Preparation of 2-methyl-2-[2-(4-nitro-phenoxy)-phenoxy]-propionicacid tert-butyl ester

To a solution of 388A (1.70 g, 7.35 mmol) and PPh₃ (5.80 g, 22.1 mmol)in anhydrous THF (35 ml) was added t-butyl 2-hydroxyisobutyrate (3.83ml, 22.1 mmol) followed by DEAD (3.47 ml, 22.1 mmol), the reactionmixture was stirred at rt for 19 h. More reagents PPh₃ (1.16 g, 4.41mmol), isobutyrate (0.77 ml, 4.41 mmol) and DEAD (0.69 ml, 4.41 mmol)were added, and the mixture was stirred for another 50 h, concentratedand purified by silica gel flash column chromatography to afford 388B(2.62 g, 96%) as a light pink crystalline solid (50%-80%CH₂Cl₂-hexanes).

388C—Preparation of 2-[2-(4-amino-phenoxy)-phenoxy]-2-methyl-propionicacid tert-butyl ester

A mixture of 388B (1.20 g, 3.21 mmol), 10% Pd/C (360 mg) in MeOH (30 ml)was stirred vigorously under a balloon of H₂ for 1.5 h, then filteredthrough celite and through 0.45μ syringe filter. The filtrate wasconcentrated to afford 388C (1.08 g, 98%) as a faintly reddish oil. LCMSFound: (M−tBu+2H)⁺=287.9.

388D—Preparation of4-{4-[2-(1-tert-butoxycarbonyl-1-methyl-ethoxy)phenoxy]-phenylamino}-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacidmethyl ester

A mixture of4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acidmethyl ester (prepared using the procedure of Example 1D) (320 mg, 1.28mmol), aniline 388C (440 mg, 1.28 mmol) and K₂CO₃ (1.77 g, 12.8 mmol) inanhydrous DMF (8 ml) was stirred at rt for 16 h. After regular workup,the residue was purified by silica gel flash column chromatography toafford 388D (651 mg, 91%) as a faintly yellow solid (0%-4%EtOAc—CH₂Cl₂). LCMS Found: (M+H)⁺=556.8; (M−tBu+2H)⁺=500.9

388—Preparation of4-(4-{2-[1-(tert-butoxycarbonylmethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester

A solution of ester 388D (482 mg, 0.866 mmol) in TFA/CH₂Cl₂/H₂O (5 ml,48/48/4) was stirred for 1 h at rt, concentrated, the resulting residuewas rotavaped with chloroform twice and CH₂Cl₂ once to give acidintermediate as a yellow solid. The solid was dissolved in1,2-dichloroethane (5 ml), glycine t-butyl ester hydrochloride (203 mg,1.21 mmol), DMAP (52.9 mg, 0.433 mmol) and DIEA (528 μl, 3.03 mmol) wereadded. The mixture was stirred 3 min until homogeneous, then EDC.HCl(249 mg, 1.30 mmol) was added. The reaction mixture was stirred for 2 h,concentrated, partitioned between EtOAc (50 ml) and 1N HCl (50 ml). Theorganic layer were washed with 1N HCl (30 ml), the combined aqueous washlayer was extracted with EtOAc (3×50 ml), the combined organic layer waswashed with brine (100 ml), dried with Na₂SO₄ and concentrated. Theresidue was purified by silica gel flash column chromatography to afforda yellow crystalline solid 388 (372 mg, 70%)(10%-25% EtOAc—CH₂Cl₂). LCMSFound: (M+H)⁺=613.6; (M−tBu+2H)⁺=558.2

EXAMPLE 389

4-(4-{2-[1-(Carboxymethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester

A solution of ester 388 (292 mg, 0.476 mmol) in TFA/CH₂Cl₂/H₂O (5 ml,48/48/4) was stirred for 2 h at rt, concentrated and purified by silicagel flash column chromatography to afford the title compound (233 mg,89%) as a crystalline yellow powder (4%-12% MeOH—CH₂Cl₂). LCMS Found:(M+H)⁺=558.0

EXAMPLE 390

3-Cyano-4-(4-{2-[1-(ethylcarbamoylmethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester

To a solution of acid from Example 388 (29.2 mg, 0.0524 mmol), EtNH₂ (2Nin THF, 31.4 μl, 0.0629 mmol) and DIEA (23.7 μl, 0.136 mmol) indichloroethane (1.2 ml) at −10° C. was added EDC.HCl (12.1 mg, 0.0629mmol). The reaction mixture was stirred at rt for 2 h, concentrated andpurified by silica gel flash column chromatography to afford the titlecompound (16.2 mg, 53%) as a yellow solid (4%-10% MeOH—CH₂Cl₂). LCMSFound: (M+H)⁺=585.0

EXAMPLE 391

4-(1-Benzyl-piperidin-4-ylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester

The title compound was prepared from4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acidmethyl ester (prepared using the procedure of Example 1D) (65.0 mg,0.246 mmol) and 4-amino-1-benzylpiperidine (52.6 μl, 0.258 mmol) by aroute analogous to that used for the preparation of compound 388D. It(100 mg, 97%) was a white crystalline solid. LCMS Found: (M+H)⁺=418.2

EXAMPLE 392

3-Cyano-5-methyl-4-(4-phenoxy-benzenesulfonyl)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethylester 392A—Preparation of 4-phenoxybenzensulfonic acid, sodiumsalt

A mixture of 4-phenoxybenzensulfonyl chloride (0.46 g, 1.72 mmol),Na₂SO₃ (0.22 g, 1.75 mmol), Na₂CO₃ (0.20 g, 1.89 mmol) in water (3 ml)was heated at 100° C. for 0.5 h, small amount of precipitate wasfiltered off, white needles crystallized from filtrate, filtered, thesolid was washed with small amount of water to give 392A (250 mg, 57%).

392B—Preparation of3-Cyano-5-methyl-4-(4-phenoxy-benzenesulfonyl)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester

4-Chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acidethyl ester (Example 1D) (27.0 mg, 0.10 mmol) and 392A (26.0 mg, 0.056mmol) were dissolved in DMF (0.5 ml). The reaction mixture was stirredat rt for 2 h, evaporated, the residue was purified by silica gel flashcolumn chromatography to afford 392B (20 mg, 43%) (0%-10%EtOAc—hexanes). LCMS Found: (M+H)⁺=461.9

EXAMPLE 393

3-Cyano-5-methoxy-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester 393A—Preparation of(1,3-dioxo-1,3-dihydro-isoindol-2-ylamino)-acetic acid ethyl ester

A mixture of 2-amino-isoindole-1,3-dione (5.0 g, 30.9 mmol), ethylbromoacetate (10.32 g, 61.8 mmol), K₂CO₃ (8.5 g, 61.8 mmol) in DMA (38ml) was heated at 80° C. for 7 h. After cooling to rt, the mixture wasfiltered, and the filtrate was diluted with EtOAc, washed with water andbrine, dried and concentrated. The residue was treated with EtOAc andhexanes to give 393A (4.4 g, 57%) as yellow crystals.

393B—Preparation of2-{[(1,3-dioxo-1,3-dihydro-isoindol-2-yl)ethoxycarbonylmethyl-amino]-methylene}-malonicacid diethyl ester

A mixture of 393A (2.4 g, 9.7 mmol) and 2-ethoxycarbonyl-but-2-enedioicacid diethyl ester (2.49 g, 10.2 mmol) was heated at 120° C. overnight.The resulting 393B was directly used in the next step withoutpurification.

393C—Preparation of1-(2-Ethoxycarbonyl-benzoylamino)-3-hydroxy-1H-pyrrole-2,4-dicarboxylicacid diethyl ester

To a solution of 393B (850 mg, 2 mmol) in EtOH (5 ml) at rt was added Nametal (92 mg, 4 mmol), after stirring for 2 h, more Na metal (60 mg, 2.6mmol) was added. The mixture was stirred at rt overnight. SaturatedNH₄Cl was added, the PH was adjusted to 4 with 1N H₂SO₄. The mixture wasextracted with EtOAc, dried with Na₂SO₄ and concentrated to give desiredproduct 393C.

393D—Preparation of1-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-methoxy-1H-pyrrole-2,4-dicarboxylicacid diethyl ester

A mixture of 393C (0.84 g, 2 mmol) and K₂CO₃ (1.0 g, 7.25 mmol) inacetone (5 ml) was heated at 50° C. for 30 min, then cooled to rt.Dimethyl sulfate (0.29 ml, 3.0 mmol) was added, the resulting mixturewas heated at 40° C. until starting material consumed, quenched withbrine and extracted with EtOAc. The organic layer was dried andconcentrated, the residue was purified by silica gel flash columnchromatography to afford 393D (0.58 g, 74% for 3 steps from 393B) (0%-5%EtOAc—CH₂Cl₂).

393E—Preparation of 1-amino-3-methoxy-1H-pyrrole-2,4-dicarboxylic aciddiethyl ester

A mixture of 393D (0.58 g, 1.58 mmol) and NH₂NH₂ (60 μl, 2.21 mmol) inEtOH (5 ml) was stirred at rt overnight, filtered through Celite, thefiltrate was concentrated and the residue was purified by silica gelflash column chromatography to give 393E (0.30 g, 75%) (0%-5%EtOAc—CH₂Cl₂).

393F—Preparation of3-cyano-4-hydroxy-5-methoxy-pyrrolo[1,2-b]pyridazine-6-carboxylic acidethyl ester

To a mixture of amine 393E (0.34 g, 1.33 mmol) in toluene (2.6 ml) wasadded 3,3-dimethoxy-propionitrile (0.4 ml, 2.66 mmol) and TsOH.H₂O (50mg, 0.266 mmol), the mixture was heated at 80° C. for 4 h, then DBU(0.404 mg, 2.66 mmol) was added, and heated for another 0.5 h. Theresidue was purified by silica gel flash column chromatography to give0.46 g of crude 393F (10% MeOH—CH₂Cl₂).

393G—Preparation of4-chloro-3-cyano-5-methoxy-pyrrolo[1,2-b]pyridazine-6-carboxylic acidethyl ester

A mixture of 0.46 g of crude 393F in POCl₃ (5 ml) was heated at 110° C.for 1 h. Excess of POCl₃ was removed on a rotary evaporator, the residuewas dissolved in CH₂Cl₂, washed with aqueous NaHCO₃, dried andconcentrated to give 0.37 g of crude 393G which was used in next stepwithout purification.

393—Preparation of3-cyano-5-methoxy-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester

The compound 393 was prepared from 0.37 g of crude4-chloro-3-cyano-5-methoxy-pyrrolo[1,2-b]pyridazine-6-carboxylic acidethyl ester and 4-phenoxy-phenylamine (0.24 g, 1.30 mmol) by a routeanalogous to that used for the preparation of compound 388D. 0.28 g of393 was obtained in 49% yield for 3 steps from 393F. LCMS Found:(M+H)⁺=429.

EXAMPLE 394

3-Cyano-5-methyl-4-[4-phenoxy-3-(tetrahydro-pyran-2-yloxymethyl)-phenylamino]-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester 394A—Preparation of (2-fluoro-5-nitro-phenyl)-methanol

To a solution of 2-fluoro-5-nitro-benzoic acid (2.9 g, 15.7 mmol) in THF(20 ml) was slowly added 1M BH₃.THF (30 ml, 30 mmol) at 0° C. Thereaction mixture was stirred at rt overnight, quenched carefully withMeOH until no H₂ evolution, evaporated and redissolved in MeOH,evaporated again to give 394A (2.7 g, 100%) as a yellow solid.

394B—Preparation of 2-(2-fluoro-5-nitro-benzyloxy)-tetrahydro-pyran

To a solution of 394A (1.8 g, 10.5 mmol) in CH₂Cl₂ (10 ml) was addeddihydropyran (1.94 ml, 21.2 mmol) and PPTS (150 mg, 0.60 mmol). Thereaction was stirred at rt overnight, washed with brine, concentrated,purified by silica gel flash column chromatography to give 394B (1.88 g,70%) (100% CH₂Cl₂).

394C—Preparation of 2-(5-nitro-2-phenoxy-benzyloxy)-tetrahydro-pyran

A mixture of 394B (125 mg, 0.49 mmol), phenol (55 mg, 0.59 mmol) andt-BuOK (65 mg, 0.58 mmol) in toluene (1 ml) was heated at 120° C. for 2h. and then diluted with water, extracted with EtOAc, dried andconcentrated to give 394C (145 mg, 90%).

394D—Preparation of4-phenoxy-3-(tetrahydro-pyran-2-yloxymethyl)-phenylamine

Compound 394D was prepared from 394C in quantitative yield by a routeanalogous to that used for the preparation of compound 388C.

394—Preparation of3-cyano-5-methyl-4-[4-phenoxy-3-(tetrahydro-pyran-2-yloxymethyl)-phenylamino]-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester

Compound 394 was prepared from4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acidethyl ester (Example 1D) (160 mg, 0.61 mmol) and 394D (180 mg, 0.60mmol) by a route analogous to that used for the preparation of compound388D. It has a retention time 7.69 min. (Column: HTS, 5 u, 4.6×50 mm;Gradient: 5-100% B in 8.0 min; A=0.1% TFA/H₂O; B=0.1% TFA/CH₃CN; Runtime 10 min; Det: 215 nM; FR: 1.2 ml/min); MS Found: (M−H)⁺=525.4

EXAMPLE 395

3-Cyano-4-(3-hydroxymethyl-4-phenoxy-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester

To a solution of 394 (30 mg, 0.057 mmol) in CH₂Cl₂ (1 ml) was added TFA(300 μl). The mixture was stirred at rt for 30 min, concentrated andpurified by silica gel flash column chromatography to give the titlecompound (11 mg, 44%) (30% EtOAc—Hexanes). LCMS Found: (M+H)⁺=443.2

EXAMPLE 396

6-(1-Hydroxy-1-methyl-ethyl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile396A—Preparation of3-cyano-5-methyl-4-(4-phenoxy-phenylamino)pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester

Compound 396A (1.85 g, 85%) was prepared from4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acidethyl ester (Example 1D) (1.4 g, 5.32 mmol) and 4-phenoxy-phenylamine(1.1 g, 5.94 mmol) by a route analogous to that used for the preparationof compound 388D.

396—Preparation of6-(1-hydroxy-1-methyl-ethyl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

To a solution of 396A (1.85 g, 4.50 mmol) in THF (25 ml) was added asolution of 3M MeMgBr in Et₂O (15 ml, 45 mmol) slowly at 0° C. Thereaction mixture was warmed to rt, then heated at 50° C. for 30 min.After cooled to 0° C., the reaction was quenched with aqueous NH₄Cl,extracted with EtOAc, dried and concentrated to give 1.8 g of crude 396as a yellow solid. It has a retention time 6.49 min. (Column: HTS, 5 u,4.6×50 mm; Gradient: 5-100% B in 8.0 min; A=0.1% TFA/H₂O; B=0.1%TFA/CH₃CN; Run time 10 min; Det: 215 nM; FR: 1.2 ml/min); MS Found:(M−H)⁺=397.4

EXAMPLE 397

Trifluoro-methanesulfonic acid3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-ylester 397A—Preparation of6-hydroxy-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

34% H₂O₂ (53 μl, 0.058 mmol) was added to CH₂Cl₂ (3 ml) at −10° C., thenBF₃.Et₂O (0.64 ml, 5.0 mmol) was added. After the mixture was stirred at−10° C. for 20 min, a suspension of 396 (165 mg, 0.42 mmol) in CH₂Cl₂ (2ml) was added. The reaction was stirred at −10° C. for 5 min, thenquenched with aq Na₂SO₃, extracted with EtOAc. The organic layer wasdried, concentrated and purified by silica gel flash columnchromatography to give 397A (125 mg, 85%) (10% EtOAc—CH₂Cl₂).

397—Preparation of trifluoro-methanesulfonic acid3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-ylester

To a solution of 397A (32 mg, 0.090 mmol) in CH₂Cl₂ (1 ml) was addedTf₂O (18 μl, 0.099 mmol) at −10° C. The reaction mixture was stirred for5 min, diluted with EtOAc, washed with brine, dried and concentrated togive 397 (42 mg, 95%) LCMS Found: (M+H)⁺=489.0

EXAMPLE 398

6-(1-Hydroxy-1-methyl-ethyl)-5-methoxy-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

The title compound (170 mg, 98%) was prepared from 393 (180 mg, 0.42mmol) by a route analogous to that used for the preparation of compound396. It has a retention time of 6.49 min. (Column: HTS, 5 u, 4.6×50 mm;Gradient: 5-100% B in 8.0 min; A=0.1% TFA/H₂O; B=0.1% TFA/CH₃CN; Runtime 10 min; Det: 215 nM; FR: 1.2 ml/min); MS Found: (M−H)⁺=413.3

EXAMPLE 399

6-Hydroxy-5-methoxy-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

The title compound (26 mg, 76%) was prepared from Example 398 (38 mg,0.092 mmol) by a route analogous to that used for the preparation ofcompound 397A. It has a retention time of 6.08 min. (Column: HTS, 5 u,4.6×50 mm; Gradient: 5-100% B in 8.0 min; A=0.1% TFA/H₂O; B=0.1%TFA/CH₃CN; Run time 10 min; Det: 215 nM; FR: 1.2 ml/min); MS Found:(M+H)⁺=373.2

EXAMPLE 400

5,6-Dimethoxy-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

A mixture of compound from Example 399 (14 mg, 0.038 mmol), dimethylsulfate (4 μl, 0.042 mmol), K₂CO₃ (14 mg, 0.101 mmol) in acetone (0.5ml) was stirred at rt overnight. After regular workup, the titlecompound (13 mg, 88%) was obtained after silica gel flash columnchromatography (100% CH₂Cl₂). LCMS Found: (M+H)⁺=387.1

EXAMPLE 401

6-(4-Methoxy-phenyl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

A mixture of Example 397 (24 mg, 0.049 mmol), 4-methoxybenzeneboronicacid (11 mg, 0.072 mmol), Pd(OAc)₂ (1.0 mg, 0.0045 mmol),2-(dicyclohexylphosphino) biphenyl (5.0 mg, 0.014 mmol) and K₃PO₄ (20mg, 0.10 mmol) in toluene (0.5 ml) was degassed with argon. The mixturewas heated at 90° C. for 20 min, then directly purified by silica gelflash column chromatography to give title compound (20 mg, 92%) (10%EtOAc—hexanes). LCMS Found: (M+H)⁺=447.2

EXAMPLE 402

5-Methyl-4-(4-phenoxy-phenylamino)-6-phenyl-pyrrolo[1,2-b]pyridazine-3-carbonitrile

The title compound was prepared from Example 397 (30 mg, 0.062) andbenzeneboronic acid (12 mg, 0.098 mmol) by a route analogous to thatused for the preparation of Example 401. LCMS Found: (M+H)⁺=417.2

EXAMPLE 403

3-Cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester 403A—Preparation of 2,4-dicarboethoxypyrrole

To a stirred solution of ethyl isocyanoacetate (0.02 mol, 2.3 mL) andDBU (3.0 g, 0.02 mol) in THF (30 mL) was added a solution offormaldehyde (0.6M THF solution, 16.6 mL, 0.01 mole) at 45-50° C. for aperiod of 15 min. After stirring for 5 hr at the same temperature, thereaction mixture was neutralized with HOAc and the solvents were removedunder reduced pressure. The resulting oil was partitioned between satd.aq. NaHCO₃ and EtOAc. The EtOAc layer was separated, dried with Na₂SO₄and concentrated in vacuo to obtain a viscous oil which waschromatographed on silica (20% EtOAc—hexanes) to give 403A (0.80 g,38%). MS Found: (M+H)⁺=212.0;

¹H NMR (CDCl₃) δ 9.8 (br, 1H), 7.56 (dd, J₁=3.2 Hz, J₂=1.5 Hz, 1H), 7.(dd, J₁=3.2 Hz, J₂=1.5 Hz, 1H), 4.3 (m, 4H), 1.3 (m, 6H).

403B—Preparation of3-cyano-4-hydroxy-pyrrolo-[1,2-b]pyridazine-6-carboxylic acid ethylester

Pyrrole 403A (211 mg, 1.0 mmol) in DMF (1 mL) was slowly added to asuspension of NaH (60% suspension in mineral oil, 40 mg, 1.0 mmol,) inDMF (1 mL) at 0° C. under N₂. The resulting mixture was stirred at 0° C.for 15 min. and allowed to warm to RT. After stirring at RT for another15 min, the reaction mixture was cooled to 0° C. andO-mesitylenesulfonylhydroxylamine (C. Johnson, et al, J. Org. Chem.,1974, 39, 2458) (225 mg, 1.0 mmol) was added. The resulting mixture wasallowed warm to RT and stirred for 14 hr and poured into satd. aq. NH₄Clsolution (20 mL). The organic materials were then extracted with EtOAc(2×10 mL), dried with Na₂SO₄ and concentrated in vacuo to obtain anapproximately 1:1 mixture of starting material and aminopyrrole whichwas dried in vacuo for 12 h and directly used in the next step.

The crude material obtained from the above reaction (200 mg),diethoxypropionitrile (0.2 mL) and TsOH (38 mg) in toluene (10 mL) wereheated at 100° C. until the ninhydrin positive starting material almostdisappeared on TLC. The reaction mixture was then allowed to cool to RTand DBU (0.04 ml, 3.0 mmol,) was added and heated at 80° C. for 6 h.Reaction mixture was then allowed to cool to RT and concentrated invacuo to obtain a viscous oil which was redissolved in 5% MeOH/CH₂Cl₂(10 mL) and washed with water (2×10 mL). The organic layer wasseparated, dried with Na₂SO₄ and concentrated in vacuo to obtain a darkbrown residue which was chromatographed on silica. After removing thelow polar impurities (10-20% EtOAc—hexanes), partially pure product 403B(99 mg, 43%) was obtained by eluting with 10% MeOH/EtOAc. MS Found:(M+H)⁺=232.1

403C. Preparation of4-chloro-3-cyano-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester

Compound 403C was prepared from 403B by a route analogous to that usedfor the preparation of 393G.

403—Preparation of3-cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester

Compound 403 was prepared from 403C and 4-phenoxy-phenylamine by a routeanalogous to that used for the preparation of 388D. Yield: 53%. MSFound: (M+H)⁺=399.2; ¹H NMR (CDCl₃) δ 8.1 and 7.9 (s, 1H each), 7.3 (m,2H), 7.26 (m, 2H), 7.2 (m, 2H), 7.15 (m, 4H), 6.2 (s, 1H), 4.25 (q,J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).

EXAMPLES 404-405

404)7-Bromo-3-cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester

or

405)7-Chloro-3-cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester

General procedure for the preparation of 5-halo-2,4-dicarboethoxypyrrole

To a solution of 2,4-dicarboethoxypyrrole 403A (211 mg, 1 mmol) in HOAc(2 mL) N-halosuccinamide (1.5 mmol) was added followed by CF₃SO₃H (0.1mL). The resulting mixture was stirred at RT for 4 h, then poured intowater. The product was extracted with CH₂Cl₂ (2×10 mL). CH₂Cl₂ extractswere combined and washed with saturated aq. NaHCO₃ (3×10 mL), saturatedNa₂S₂O₃ and water. The CH₂Cl₂ layer was dried with Na₂SO₄ andconcentrated in vacuo. The resulting residue was purified on silica(10-15% EtOAc—hexanes)

404A—5-bromo-2,4-dicarboethoxypyrrole

Yield: 66%; ¹H NMR (CDCl₃) δ 10.1 (br, 1H), 7.3 (s, 1H), 4.32 and 4.39(q, J=7.1 Hz, 2H each), 1.38 (m, 6H)

405A—5-chloro-2,4-dicarboethoxypyrrole

Yield: 71%; ¹H NMR (CDCl₃) δ 9.7 (br s, 1H), 7.28 (s, 1H), 4.3 (m, 4H),1.15 and 1.27 (t, J=7.1 and 7.05, 3H each)

Preparation of3-cyano-7-halo-4-hydroxy-pyrrolo-[1,2-b]pyridazine-6-carboxylic acidethyl ester

Compounds 404B and 405B were prepared respectively from 404A and 405A bya route analogous to that used for the preparation of 403B.

404B—7-Bromo-3-cyano-4-hydroxy-pyrrolo-[1,2-b]pyridazine-6-carboxylicacid ethyl ester

Yield: 36%. MS Found: (M+H)⁺=309.2

405B—7-Chloro-3-cyano-4-hydroxy-pyrrolo-[1,2-b]pyridazine-6-carboxylicacid ethyl ester

Yield: 31%. MS Found: (M+H)⁺=266.1

Preparation of4-chloro-3-cyano-7-halo-pyrrolo-[1,2-b]pyridazine-6-carboxylic acidethyl ester

Compounds 404C and 405C were prepared respectively from 404B and 405B bya route analogous to that used for the preparation of 393G.

Preparation of7-halo-3-cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester

Compounds 404 and 405 were prepared respectively from 404C and 405C with4-phenoxy-phenylamine by a route analogous to that used for thepreparation of 388D.

404—7-Bromo-3-cyano-4-(4-phenoxy-phenylamino0-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester

Yield: 47%. MS Found: (M+H)⁺=477.1; ¹H NMR (CDCl₃) δ 8.07 (s, 1H), 7.4(m, 2H), 7.3 (m, 2H), 7.18 (m, 2H), 7.1 (m, 4H), 6.2 (s, 1H), 4.3 (q,J=7.1 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H)

405—7-Chloro-3-cyano-4-(4-phenoxy-phenylamino0-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester

Yield: 51%. MS Found: (M+H)⁺=432.1; ¹H NMR (CDCl₃) δ 8.07 (s, 1H), 7.4(m, 2H), 7.32 (m, 2H), 7.18 (m, 2H), 7.1 (m, 4H), 6.2 (s, 1H), 4.3 (q,J=7.0 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H)

EXAMPLE 406

3-Cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-7-carboxylicacid ethyl ester 406A—Preparation of 5-formyl-1H-pyrrole-2-carboxylicacid ethyl ester

POCl₃ (7.8 ml, 83.7 mmol) was slowly added to DMF (7.0 ml, 90.4 mmol) at0° C. under argon. After addition, the mixture was stirred at rt for 5min, then anhydrous CH₂Cl₂ (25 ml) was added. To the resulting mixtureat 0° C. was added a solution of 1H-pyrrole-2-carboxylic acid ethylester (10.53 g, 75.64 mmol) in CH₂Cl₂ (25 ml). The reaction mixture wasstirred for 10 min, then refluxed for 15 min, after cooling down to rt,it was poured into ice-water, saturated Na₂CO₃ was added until no morebubbles forming. The mixture was extracted with EtOAc (3×150 ml), thecombined EtOAc layer was washed with saturated NaHCO₃ (2×100 ml),saturated Na₂CO₃ (1×100 ml) and brine (1×150 ml), dried over MgSO₄,concentrated to give pure 19A (8.0 g, 63.3%) as a brownish solid.

406B—Preparation of 1H-pyrrole-2,5-dicarboxylic acid diethyl ester

To a mixture of 406A (167 mg, 1.0 mmol), KCN (325.6 mg, 5.0 mmol) inanhydrous EtOH (20 ml) was added AcOH (85.9 μl, 1.5 mmol) followed byactivated MnO₂ (1.643 g, 20 mmol). The reaction was stirred overnight.After workup, the residue was purified by silica gel flash columnchromatography to give 406B (162 mg, 77%) as a pinkish solid (25%EtOAc—hexanes).

406C—Preparation of 1-amino-1H-pyrrole-2,5-dicarboxylic acid diethylester

NaH (60% in mineral oil, 154.3 mg, 3.86 mmol) was rinsed with hexanes (5ml), then anhydrous DMF (10 ml) was added, to this suspension 406B (0.68g, 3.22 mmol) was added portionwise at 0° C., and the mixture wasstirred for 1 h from 0° C. to rt. O-(2,4-dinitro-phenyl)-hydroxylamine(705.6 mg, 3.54 mmol) was added in two portions at 0° C., the reactionmixture was stirred at rt overnight. Water (50 ml) was added, themixture was extracted with EtOAc (3×25 ml), the combined organic layerwas washed with water (4×20 ml) and brine (1×20 ml), dried andconcentrated. The residue was purified by silica gel flash columnchromatography to give 406C (480 mg, 66%) as a yellow solid (25%EtOAc—hexanes).

406D—Preparation of1-(dimethylamino-methyleneamino)-1H-pyrrole-2,5-dicarboxylic aciddiethyl ester

A mixture of 406C (482 mg, 2.13 mmol) and dimethoxymethyl-dimethyl-amine(1.5 ml) in anhydrous DMF (5 ml) was heated at 105° C. overnight. Afterthe solvent was removed, the residue was purified by silica gel flashcolumn chromatography to give 406D (546 mg, 91%) as pink crystals (25%EtOAc—hexanes). MS Found: (M+H)⁺=282.1

406E—Preparation of3-cyano-4-hydroxy-pyrrolo[1,2-b]pyridazine-7-carboxylic acid ethyl ester

To a solution of n-BuLi (1.6 M in hexanes) (290 μl, 0.465 mmol) in THF(1 ml) was added a solution of CH₃CN (19.1 mg, 0.465 mmol) in THF (2 ml)dropwise at 0° C. The mixture was stirred for 20 min, then a solution of406D (62 mg, 0.221 mmol) in THF (5 ml) was added. After the mixture wasstirred for 40 min, the reaction temperature was lowered to −78° C.,AcOH (38 μl, 0.663 mmol) was added. The reaction mixture was thenstirred at rt overnight. Solvent was removed, 406E (26 mg, 50%) wasobtained as a yellowish solid after preparative HPLC purification. LCMSFound: (M+H)⁺=232.

406—Preparation of3-cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-7-carboxylicacid ethyl ester

Compound 406E (110 mg, 0.476 mmol) was heated in POCl₃ (1 ml) at 83-100°C. for 2 h. Excess POCl₃ was removed on a rotary evaporator, and theresidue was stripped with CH₂Cl₂ (2 ml). To the solid residue was addedDMF (5 ml), K₂CO₃ (690 mg, 5 mmol) and 4-phenoxy-phenylamine (353 mg,1.91 mmol) at 0° C. The reaction mixture was degassed and stirred at rtovernight. Solid was filtered off and the filtrate was concentrated, theresidue was purified by silica gel flash column chromatography to givethe 406 (147 mg, 78%) as a yellow solid (25% EtOAc—Hexanes). LCMS Found:(M+H)⁺=398.6

EXAMPLE 407

7-Hydroxymethyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

To a solution of 406 (39.8 mg, 0.1 mmol) in THF (2 ml) was added DIBAL-H(1.0 M in CH₂Cl₂, 0.2 ml, 0.2 mmol) at −78° C. The reaction mixture wasstirred at this temperature for 6 h, then at 0° C. for 2 h, quenchedwith water (0.1 ml). The solid was filtered off, and the filtrate wasconcentrated. The residue was purified by preparative TLC to give thetitle compound (22.8 mg, 64%) as a brown solid (2.5% MeOH—CH₂Cl₂). LCMSFound: (M+H)⁺=357.

EXAMPLE 408

3-Cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-7-carboxylicacid

A mixture of 406 (15.6 mg, 0.039 mmol) and 1N NaOH (150 μl, 0.15 mmol)in EtOH (5 ml) was stirred at 50-70° C. for 15 h. 1N HCl (150 μl, 0.15mmol) was added, solvent was removed, and the residue was purified bypreparative TLC to give the title compound (14.1 mg, 98%) as a tansolid. LCMS Found: (M+H)⁺=371.1

EXAMPLE 409

3-Cyano-5,7-dimethyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester 409A—Preparation of1-amino-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester

Compound 409A was prepared from 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylicacid diethyl ester by a route analogous to that used for the preparationof compound 406C.

409B—Preparation of1-(dimethylamino-methyleneamino)-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylicacid diethyl ester

Compound 409B was prepared from 409A by a route analogous to that usedfor the preparation of compound 406D.

409C—Preparation of3-cyano-4-hydroxy-5,7-dimethyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester

Compound 409C was prepared from 409B by a route analogous to that usedfor the preparation of compound 406E.

409—Preparation of3-cyano-5,7-dimethyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester

Compound 409D was prepared from 409B by a route analogous to that usedfor the preparation of compound 406. MS Found: (M+H)⁺=427.1

EXAMPLE 410

5-Methyl-6-(4-methyl-piperazin-1-ylmethyl)-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

A mixture of6-formyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 8) (27 mg, 0.073 mmol) and 1-methyl-piperazine (8.1 μl, 0.073mmol) in CH₂Cl₂ (2.5 ml) was stirred for 48 h, then treated withNaBH(OAc)₃ (46.4 mg, 0.2 mmol) and stirred for 24 h. The mixture wasdiluted with CHCl₃, washed with saturated NaHCO₃ and H₂O, dried withNa₂SO₄. Concentrated in vacuo and purified by prep. TLC to give thetitle compound (22 mg, 66%) (20% MeOH—CHCl₃). It has a retention time of4.90 min (standard LCl method, 8 min run). LCMS Found: (M+H)⁺=453.1

EXAMPLE 411

[3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-ylmethoxy]-aceticacid ethylester

A mixture of6-hydroxymethyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 3B) (36 mg, 0.097 mmol), bromo-acetic acid ethyl ester (24 mg,0.146 mmol) and K₂CO₃ (67 mg, 0.48 mmol) in DMF (0.6 ml) was heated at80° C. for 45 min, then diluted with CHCl₃ (50 ml), washed with H₂O(2×20 ml), dried with Na₂SO₄. Concentrated in vacuo and purified byprep. TLC to give the title compound (12.2 mg, 28%) (50% EtOAc—hexanes).It has a retention time of 6.62 min (standard LCl method, 8 min run). MSFound: (M+H)⁺=457.1

EXAMPLE 412

412A—Preparation of N-hydroxyacetamidine

To a solution of acetonitrile (1 ml, 19 mmol) in ethanol (6 ml) wasadded hydroxylamine (50 wt % in H₂O, 5.0 ml, 76 mmol). The solution washeated to reflux for 1.5 h. Concentration of the reaction mixture invacuo yielded 412A (1.4 g, 100%) as a white solid. ¹HNMR (DMSO, 400MHz): δ 3.32 (s, 3H), 5.33 (bs, 2H), 8.64 (s, 1H);

412B—Preparation of3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carbonylchloride

To a slurry of Example 9 (83 mg, 0.21 mmol) in 3 mL of dichloromethaneat 0° C. was added oxalyl chloride (28.2 μL, 0.32 mmol) followed by 5 μLof DMF. The reaction was warmed to room temperature and then cooled to0° C. once the reaction became homogenous. After 20 min, another 9 μL(0.5 eq) of oxalyl chloride was added. Thin-layer chromatographyanalysis indicated that most of the starting carboxylic acid wasconsumed. The reaction was concentrated in vacuo with toluene (2×5 mL),dried under vacuum and then used without further purification.

412—Preparation of3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carbonyl-N-hydroxylacetamidine

A solution of Example 412B (84.5 mg, 0.21 mmol) in CH₂Cl₂ (2.5 ml) wasadded to a solution 412A (15.5 mg, 0.21 mmol) and Hunig's base (57 mg,0.44 mmol) in CH₂Cl₂ (2 ml) at 0° C. TLC shows that reaction completedimmediately. The reaction mixture was diluted with CHCl₃ (50 ml), washedwith saturated NaHCO₃, dried with Na₂SO₄. Concentrated in vacuo andpurified by prep. TLC to give the title compound (40 mg, 43%) as paleyellow flakes (10% MeOH—CHCl₃). It has a retention time of 5.92 min(standard LCl method, 8 min run). MS Found: (M+H)⁺=441.0

EXAMPLE 413

6-(Hydroxyimino-methyl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

To a slurry of6-formyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 8) (37 mg, 0.1 mmol) in MeOH (1 ml) was added H₂NOH (50% wt. inH₂O, 14 μl 0.2 mmol) at rt. The heterogeneous mixture was stirredovernight, then diluted with H₂O (5 ml) and filtered, the solid wasdissolved in MeOH, which was concentrated to give title compound (30 mg,78%) as a yellow powder. It has a retention time of 6.18 min (standardLCl method, 8 min run). MS Found: (M+H)⁺=384.2

EXAMPLE 414

N-Benzyl-N-[3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-ylmethyl]-acetamide414A—Preparation of6-(benzylamino-methyl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

Benzylamine (10 μl, 0.09 mmol) was added to a solution of6-formyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile(Example 8) (32 mg, 0.087 mmol) in CH₂Cl₂/DMF (10/1) (2.2 ml). Themixture was stirred overnight, then treated with NaBH(OAc)₃ (55 mg, 0.26mmol) and stirred overnight again. Diluted with CHCl₃, washed withsaturated NaHCO₃ and H₂O, dried with Na₂SO₄. Concentrated in vacuo andpurified by prep. TLC to give the title compound (28 mg, 70%) asyellow-green oil (10% MeOH—CHCl₃). It has a retention time of 6.46 min(standard LCl method, 8 min run). LCMS Found: (M+H)⁺=460.20

414—Preparation ofN-benzyl-N-[3-cyano-5-methyl-4-(4-phenoxyphenylamino)-pyrrolo[1,2-b]pyridazin-6-ylmethyl]-acetamide

To a solution of 414A (28 mg, 0.06 mmol) and Et₃N (17 μl, 0.12 mmol) inCH₂Cl₂ (2 ml) was added Ac₂O (11 μl, 0.12 mmol), reaction completedimmediately. After regular workup, the residue was purified by prep. TLCto give the 414 (25 mg, 83%) as light yellow powder (2% MeOH—CHCl₃). Ithas a retention time of 7.23 min (standard LCl method, 8 min run). MSFound: (M+H)⁺=502.0

EXAMPLE 415

N-[3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-yl]-methanesulfonamide

To a slurry of6-amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (Example 11B) (14 mg, 0.035 mmol) in CH₂Cl₂ (2 ml) wasadded N-methyl morpholine (12.3 μl, 0.113 mmol) followed by MsCl (4.5μl, 0.057 mmol). The reaction mixture was stirred overnight, 10% citricacid (3 ml) was added. The resulting mixture was extracted with CHCl₃(10 ml), the organic layer was separated and dried with Na₂SO₄,concentrated to give the title compound (6.9 mg, 45%). It has aretention time of 6.01 min (standard LCl method, 8 min run). MS Found:(M+H)⁺=434.0

EXAMPLE 416

5-Methyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

The amidoxime from Example 412 (58 mg, 0.13 mmol) was dissolved in THF(3 ml) at 50° C., a solution of 1N TBAF in THF (0.64 ml, 0.64 mmol) wasadded. The reaction mixture was stirred at rt overnight, then at 60° C.for 1 h. After regular workup, the residue was purified by prep. TLC togive the title compound (17.6 mg, 32%) (20% EtOAc—hexanes). It has aretention time of 7.10 min (standard LCl method, 8 min run). MS Found:(M+H)⁺=423.2

EXAMPLE 417

3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methoxy-methyl-amide

To a solution of3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carbonylchloride (Example 412B) (181 mg, 0.45 mmol) in CH₂Cl₂ (3 ml) was addedEt₃N (160 μl, 1.13 mmol) followed by O,N-dimethylhydroxyaminehydrochloride (44 mg, 0.45 mmol) in one portion. The mixture was stirredovernight, diluted with CHCl₃ (20 ml), washed with water (2×20 ml),dried with Na₂SO₄. Concentrated in vacuo and purified by prep. TLC togive the title compound (138 mg, 72%) (50% EtOAc—hexanes). It has aretention time of 6.45 min (standard LCl method, 8 min run). LCMS Found:(M+H)⁺=428.1

EXAMPLE 418

5-Methyl-4-(4-phenoxy-phenylamino)-6-propynoyl-pyrrolo[1,2-b]pyridazine-3-carbonitrile

To a solution of amide from Example 417 (60 mg, 0.14 mmol) in THF (2 ml)at 0° C. was added ethynylmagnesium bromide (0.5 M in THF, 1.4 ml, 0.7mmol). The reaction mixture was warmed to rt for 2 h, then heated at 50°C. for 2 h, and at rt overnight. Diluted with ether, washed withsaturated NaHCO₃, dried with Na₂SO₄. Concentrated in vacuo and purifiedby prep. TLC to give the title compound (30 mg, 32%) (5% MeOH—CHCl₃). Ithas a retention time of 6.82 min (standard LCl method, 8 min run). LCMSFound: (M+H)⁺=393.2

EXAMPLE 419

419A—Preparation of N-hydroxy-morpholine-4-carboxamidine

The title compound was prepared from the reaction of morpholine nitrileand hydroxylamine (equimolar amounts) by a route analogous to that usedfor the preparation of Example 412A to yield 419A in quantitative yield.¹H NMR (400 MHz, DMSO-d₆) δ 8.33 (s, 1H), 5.18 (S, 2H), 3.57 (m, 4H),2.93 (m, 4H)

419—Preparation of3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-carbonyl-N-hydroxylmorpholinyl-acetamidine

To a solution of N-hydroxy-morpholine-4-carboxamidine (Example 419A)(20.2 mg, 0.13 mmol) and Hunig's base (45 μl, 0.26 mmol) in DMF (1 ml)at −5° C. was added a solution of3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carbonylchloride (Example 412B) (51 mg, 0.12 mmol) in DMF (1 ml) via syringe.The reaction mixture was warmed to rt, after 20 min, diluted with EtOAc,poured into water (50 ml), extracted with EtOAc (2×50 ml). The combinedextracts were dried with Na₂SO₄, concentrated in vacuo and purified byprep. TLC to give the title compound (23 mg, 37%) (5% MeOH—CHCl₃). Ithas a retention time of 5.79 min (standard LC1 method, 8 min run). LCMSFound: (M+H)⁺=512.2.

EXAMPLE 420

5-Methyl-6-(3-morpholin-4-yl-[1,2,4]oxadiazol-5-yl)-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

To a solution of compound from Example 419 (24 mg, 0.047 mmol) in amixed solvents of EtOH (0.5 ml) and toluene (1 ml) was added 2M Na₂CO₃(2 ml, 2 mmol). The reaction mixture was stirred vigorously at 100° C.for 30 min, the organic layer was separated, the aqueous layer wasextracted with EtOAc (2×5 ml), the combined organic layer was dried withNa₂SO₄, concentrated in vacuo and purified by silica gel column to givethe title compound (10.2 mg, 44%) (5% MeOH—CHCl₃). It has a retentiontime of 7.26 min (standard LC1 method, 8 min run). LCMS Found:M+H)⁺=494.2

EXAMPLE 421

6-(3-Methanesulfonylmethyl-[1,2,4]oxadiazol-5-yl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile421A—Preparation of N-hydroxy-2-methanesulfonyl-acetamidine

Compound 421A was prepared from methanesulfonyl-acetonitrile andhydroxylamine by a route analogous to that used for the preparation of421A in quantative yield. ¹HNMR (DMSO, 400 MHz): δ 2.99 (s, 3H), 3.82(s, 2H), 5.62 (s, 2H), 9.46 (s, 1H);

421B—Preparation of3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carbonyl-N-hydroxylmethanesulfonyl-acetamidine

Compound 421B was preparated from3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carbonylchloride (Example 412B) and 421A by a route analogous to that used forthe preparation of the compound in Example 419.

421—Preparation of6-(3-Methanesulfonylmethyl-[1,2,4]oxadiazol-5-yl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

Compound 421 (7.5 mg, 47%) was prepared from 421B (17 mg, 0.032 mmol) bya route analogous to that used for the preparation of the compound inExample 420. It has a retention time of 6.41 min (standard LC1 method, 8min run). LCMS Found: (M+H)⁺=501.1

EXAMPLE 4223-(Imino-hydrazino-methyl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Ethyl Ester

A mixture of 396A (59 mg, 0.143 mmol), H₂NNH₂ (22 mg, 0.7 mmol) inabsolute EtOH (3 ml) was heated at 100° C. in a sealed tube for 4 h.After it was cooled to rt, filtered, purified by prep. TLC to give thetitle compound (24 mg, 38%) as a light yellow crystalline solid (10%MeOH—CHCl₃). It has a retention time of 7.12 min (standard LC1 method, 8min run). LCMS Found: (M+H—H₂NNH₂)⁺=413.2

EXAMPLE 423

5-Methyl-4-(4-phenoxy-phenylamino)-6-(4-phenyl-thiazol-2-yl)-pyrrolo[1,2-b]pyridazine-3-carbonitrile423A—Preparation of 3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)pyrrolo[1,2-b]pyridazine-6-carbothioic Acid Amide

A mixture of3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid amide (Example 9) (23 mg, 0.06 mmol) and Lawessons Reagent (48.5mg, 0.12 mmol) in toluene (2 ml) was heated at 100° C. for 5 min. Afterregular workup, the residue was purified by prep. TLC to give impure423A (6 mg, 25%) (5% MeOH—CHCl₃). It has a retention time of 6.19 min(standard LC1 method, 8 min run). LCMS Found: (M+H)⁺=400.2

423—Preparation of5-Methyl-4-(4-phenoxy-phenylamino)-6-(4-phenyl-thiazol-2-yl)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

A mixture of 423A (15 mg, 0.037 mmol) and 2-bromoacetophenone (7.3 mg,0.037 mmol) in acetone (3 ml) was heated at 70° C. for 1 h. Cooled tort, hexanes (1 ml) was added, then the resulting mixture was cooled to−50° C., filtered, the solid was washed with hexanes to give thehydrobromide salt of 423 (14.9 mg, 69%) as a yellow powder. It has aretention time of 8.16 min (standard LC1 method, 8 min run). LCMS Found:(M+H)⁺=500.3

EXAMPLE 424

6-(4,5-Dihydro-1H-imidazol-2-ylamino)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile424A—Preparation of2-[3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-ylamino]-4,5-dihydro-imidazole-1-carboxylicAcid Tert-butyl Ester

A mixture of6-amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (Example 11) (49 mg, 0.125 mmol) and2-methylsulfanyl-4,5-dihydro-imidazole-1-carboxylic acid tert-butylester (25.5 mg, 0.125 mmol) in MeOH (2 ml) was heated at 70° C. for 3 h,then cooled to rt and stirred overnight. The reaction mixture wasdiluted with CHCl₃ (25 ml), washed with saturated NaHCO₃ (10 ml) driedwith Na₂SO₄. Concentrated in vacuo and purified by prep. TLC to give424A (22 mg, 97%) as pale yellow flakes (5% MeOH—CHCl₃). It has aretention time of 6.82 min (standard LC1 method, 8 min run). MS Found:(M+M)⁺=523.9

424—Preparation of6-(4,5-Dihydro-1H-imidazol-2-ylamino)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

A solution of 424A (20.2 mg, 0.038 mmol) in CH₂Cl₂ (0.3 ml) at 0° C. wastreated with TFA (300 μl) containing H₂O (20 μl). Warmed to rt, stirringcontinued for 3 h. The reaction was then concentrated in vacuo withazotropic removal of TFA and H₂O with MeOH and toluene to give the TFAsalt of 424 (19.4 mg, 95%). It has a retention time of 5.68 min(standard LC1 method, 8 min run). MS Found: (M+H)⁺=424.3

EXAMPLE 425

6-(2-Amino-4-hydroxy-4,5-dihydro-thiazol-4-ylamino)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile425A—Preparation of2-Bromo-N-[3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-yl]-acetamide

To a solution of6-amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrilehydrochloride (Example 11) (130 mg, 0.33 mmol) in CH₂Cl₂ (4 ml) at 0° C.was added hunig's base (126 μl, 0.72 mmol) followed bybromo-acetobromide (29 μl, 0.33 mmol) dropwise. The reaction mixture waswarmed to rt and stirred overnight. After regular workup, the residuewas purified by prep. TLC to give crude 425A (40 mg) (10% MeOH—CHCl₃).

425—Preparation of6-(2-Amino-4-hydroxy-4,5-dihydro-thiazol-4-ylamino)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile

A mixture of 425A (20 mg, 0.04 mmol) and thiourea (5.4 mg, 0.068 mmol)in acetone (2 ml) was heated at 70° C. for 2.5 h, then stirred at rtovernight. Filtered, the solid was washed with cold acetone and hexanes,dried to give the hydrobromide salt of 425 (14 mg, 63%) as a whitesolid. It has a retention time of 5.47 min (standard LC1 method, 8 minrun). MS Found: (M+H)⁺=472.0

EXAMPLE 426

4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Ethyl Ester 426A—Preparation of2-(2-Chloro-4-nitro-phenylsulfanyl)-1-methyl-1H-imidazole

A solution of 1-methyl-1H-imidazole-2-thiol (1.14 g, 10 mmol) in THF (50ml) under argon at 0° C. was treated with NaH (303 mg, 11.98 mmol). Themixture was warmed to rt. A solution of2-chloro-1-fluoro-4-nitro-benzene (1.76 g, 10 mmol) in THF (50 ml) wasadded, and the mixture was stirred at 70° C. for 4 h, cooled to rt.Treated with EtOAc (100 ml), the mixture was washed with H₂O (2×25 ml),1N KOH (30 ml) and brine (20 ml), dried with Na₂SO₄. Removal of thesolvent under reduced pressure gave a yellow solid. Recrystalization ofthe solid in CH₂Cl₂/hexanes gave 426A (2.31 g, 86%) as a slightyellowish solid. It has a retention time of 3.99 min (standard LC1method, 8 min run). MS Found: (M+H)⁺=270.1

426B—Preparation of3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamine

To a solution of SnCl₂.2H₂O in EtOH (10 ml) at 60° C. was added 426A(1.80 g, 6.67 mmol). Concentrated HCl (8 ml) was added and the mixturewas heated at 60° C. for 15 min. Cooled to rt, the mixture wasconcentrated under reduced pressure. The residue was basified to pH>12and extracted with EtOAc (4×50 ml). The combined organic layers werewashed with 1N KOH (20 ml), H₂O (20 ml) and brine (20 ml), dried withNa₂SO₄. Removal of the solvent under reduced pressure gave 426B (1.31 g,82%) as a white solid. The solid was used in next step without furtherpurification. It has a retention time of 3.53 min (standard LC1 method,8 min run). MS Found: (M+H)⁺=240.1

426—Preparation of4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Ethyl Ester

To a solution of4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acidether ester (Example 1D) (50 mg, 0.19 mmol) and 426B (45 mg, 0.19 mmol)in THF (1 ml) under argon was added NaH (6 mg, 0.25 mmol). The mixturewas stirred at rt for 15 min, then at reflux for 2 h, cooled to rt.Treated with EtOAc (20 ml), the mixture was washed with H₂O (3×5 ml) andbrine (5 ml), dried with Na₂SO₄. Removal of the solvent under reducedpressure followed by flash chromatography of the residue on silica gelgave a yellow solid. Recrystalization of the solid in MeOH gave 426 (39mg, 81%) as a dim yellow solid. It has a retention time of 5.92 min(standard LC1 method, 8 min run). MS Found: (M+H)⁺=467.2

EXAMPLE 427

3-Cyano-4-[2-fluoro-4-(thiazol-2-yloxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Ethyl Ester 427A—Preparation of 4-Amino-3-fluoro-phenol

Compound 427A (1.49 g, 92%) was prepared from 3-fluoro-4-nitro-phenol(2.0 g, 12.7 mmol) by a route analogous to that used for the preparationof compound 426B. It is a yellow solid and has a retention time of 4.79min (standard LC1 method, 8 min run). MS Found: (M+H)⁺=128.1

427B—Preparation of 2-Fluoro-4-(thiazol-2-yloxy)-phenylamine

A mixture of 427A (0.814 g, 6.41 mmol), 2-bromothiazole (1.0 g, 6.10mmol) and t-BuOK (0.821 g, 7.32 mmol) in DMA (25 ml) was stirred at 150°C. under argon for 1 h, then cooled to rt. Treated with EtOAc (150 ml),the mixture was washed with H₂O (50 ml), 3N NaOH (2×50 ml), H₂O (50 ml),dried with Na₂SO₄. Removal of the solvent under reduced pressurefollowed by flash chromatography of the residue on silica gel (10%-25%EtOAc-hexanes) gave 427B (1.02 g, 80%) as a colorless oil. It has aretention time of 4.02 min (standard LC1 method, 8 min run). MS Found:(M+H)⁺=211.1

427—Preparation of3-Cyano-4-[2-fluoro-4-(thiazol-2-yloxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Ethyl Ester

Compound 427 (361 mg, 83%) was prepared from4-chloro-3-cyano-5-methyl-pyrrolo]1,2-b]pyridazine-6-carboxylic acidethyl ester (Example 1D) (264 mg, 1.0 mmol) and 427B (210 mg, 1.0 mmol)by a route analogous to that used for the preparation of compound 426.It is a dim yellow solid and has a retention time of 6.76 min (standardLC1 method, 8 min run). MS Found: (M+H)⁺=438.1

EXAMPLE 428

1-{4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-d]pyridazin-6-yl}-3-(2-morpholin-4-yl-ethyl)-urea428A—Preparation of4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid

A mixture of 426 (70 mg, 0.15 mmol) and 6N NaOH (2 ml, 1.0 mmol) in amixed solvents of EtOH/THF (2/1) (3 ml) was stirred at rt for 2 days.Neutralized with concentrated HCl to PH=6, treated with EtOAc (50 ml),the mixture was washed with H₂O (2×20 ml) and brine (20 ml), dried withNa₂SO₄. Removal of the solvent gave 428A (55 mg, 93%) as a yellow solid.The product was used in next step without further purification. It has aretention time of 4.73 min (standard LC1 method, 8 min run). MS Found:(M+H)⁺=439.1

428—Preparation of1-{4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-(2-morpholin-4-yl-ethyl)-urea

A mixture of 428A (44 mg, 0.10 mmol), Et₃N (28 μl, 0.20 mmol) and DPPA(43 μl, 0.20 mmol) in dioxane (1.5 ml) was stirred under argonovernight. TMSN₃ (27 μl, 0.20 mmol) was added and the mixture was heatedto 80° C. for 2 h, then cooled to rt. 2-Morpholin-4-yl-ethylamine (26μl, 0.20 mmol) was added and the mixture was heated to 80° C. for 2 h,then cooled to rt. Removal of the solvent followed by flashchromatography of the residue on silica gel (3%-5% MeOH—CH₂Cl₂) gave agray solid. Recrystalization of the solid in CH₂Cl₂/pentane gave 428 (43mg, 75%) as a light yellow solid. It has a retention time of 3.93 min(standard LC1 method, 8 min run). MS Found: (M+H)⁺=566.1

EXAMPLE 429

3-Cyano-5-methyl-4-(5-phenoxy-pyridin-2-ylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Ethyl Ester 429A—Preparation of 5-Fluoro-2-nitro-pyridine

To concentrated H₂SO₄ at 0° C. was added 4 ml of 3% H₂O₂. To thissolution at 0° C. was added 5-fluoro-2-amino-pyridine (250 mg, 2.23mmol). The mixture was warmed to room temperature and stirred for 20 hr,then poured onto ice. The aqueous solution was extracted with EtOAc(3×30 ml). The combined organic layers were washed with water, brine anddried with Na₂SO₄. Removal of the solvent gave a light brown oil (245mg, 77%). The product was used for next step without furtherpurification.

429B—Preparation of 2-Nitro-5-phenoxy-pyridine

To a mixture of phenol (175 mg, 1.86 mmol) and t-BuOK (208 mg, 1.86mmol) in DMA (4 ml) was added a solution of 5-fluoro-2-nitro-pyridine(240 mg, 1.69 mmol) in DMA (2 ml) under argon. The deep brown mixturewas stirred at rt for 1 h. Treated with EtOAc (50 ml), the mixture waswashed with H₂O (4×10 ml) and brine (20 ml), dried with Na₂SO₄. Removalof the solvent under reduced pressure gave 429A (345 mg, 94%) as a brownoil. It has a retention time of 7.25 min (standard LC1 method, 8 minrun). MS Found: (M+H)⁺=217.0

429C—Preparation of 5-Phenoxy-pyridin-2-ylamine

Compound 429C 119 mg, 46%) was prepared from 429B (300 mg, 1.39 mmol) bya route analogous to that used for the preparation of compound 426B. Itis a dark orange oil and has a retention time of 4.28 min (standard LC1method, 8 min run). MS Found: (M+H)⁺=186.1

429—Preparation of3-Cyano-5-methyl-4-(5-phenoxy-pyridin-2-ylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Ethyl Ester

Compound 429 (21 mg, 51%) was prepared from4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acidethyl ester (Example 1D) (26 mg, 0.1 mmol) and 429C (210 mg, 1.0 mmol)by a route analogous to that used for the preparation of compound 426,DMF (1 ml) was used as solvent instead of THF. 429 is a yellow solid andhas a retention time of 6.24 min (standard LC1 method, 8 min run). MSFound: (M+H)⁺=414.2

EXAMPLE 430

3-Acetylamino-N-{3-cyano-4-[5-(2-methoxy-phenoxy)-pyridin-2-ylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-benzamide430A—Preparation of 1-(2-Methoxy-phenoxy)-4-nitro-benzene

Compound 430A (7.34 g, 100%) was prepared from 1-fluoro-4-nitro-benzene(4.23 g, 30.0 mmol) and 2-methoxy-phenol (3.72 g, 30.0 mmol) by a routeanalogous to that used for the preparation of compound 429B. It is abright yellow solid.

430B—Preparation of 4-(2-methoxy-phenoxy)-phenylamine

A mixture of 430A (7.34 g, 29.9 mmol) and 10% Pd/C (1.47 g, 20 wt %, 50wt % H₂O) was stirred under H₂ balloon in MeOH (60 ml) for 12 h. Thecatalyst was removed by filtration on celite. The filtrate wasconcentrated in vacuo to give 430B (6.40 g, 99%) as a white solid. Ithas a retention time of 3.77 min (standard ∠Cl method, 8 min run). MSfound: (M+H)⁺=216.1

430C—Preparation of3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Methyl Ester

Compound 430C (1.81 g, 85%) was prepared from4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acidmethyl ester (prepared using the procedure of Example 1D) (1.25 g, 5.0mmol) and 430B (1.08 g, 5.0 mmol) by a route analogous to that used forthe preparation of compound 388D. It is a white solid, and has aretention time of 6.74 min (∠Cl, 8 min run). MS found, (M+H)⁺=429.2

430D—Preparation of3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid

A mixture of 430C (1.60 g, 3.73 mmol) and 6N NaOH (5 ml, 30 mmol) in amixed solvent of MeOH/THF (20 ml, 1/1) was heated at reflux for 2 h,cooled to rt. Removed half of the solvent in vacuo. The residue wastreated with H₂O (30 ml), washed with CH₂Cl₂ (3×50 ml). The aqueouslayer was acidified to PH=5 and extracted with EtOAc (3×50 ml). Thecombined organic layers were washed with H₂O (2×30 ml) and brine (30ml), dried with Na₂SO₄. Removal of the solvent under reduced pressuregave 430D (1.47 g, 95%) as a yellow powder. It has retention time of5.88 min (∠Cl, 8 min. run). MS Found: (M+H)⁺=415.2.

430E—Preparation of{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicAcid Benzyl Ester

A mixture of 430D (1.24 g, 3.0 mmol), Et₃N (1.67 ml, 12.0 mmol) and DPPA(1.29 ml, 6.0 mmol) in 1,4-dioxane (20 ml) was stirred at rt for 16 hunder argon. Benzyl alcohol (1.86 ml, 18.0 mmol) was added. Theresulting mixture was heated to 80° C. for 2.5 h, cooled to rt. Removalof the solvent in vacuo gave a brown oil. Treated with EtOAc (100 ml),the mixture was washed with H₂O (3×30 ml) and brine (20 ml), dried withNa₂SO₄. Removal of the solvent followed by flash chromatography of theresidue on silica gel (CH₂Cl₂ first, then 20% EtOAc-hexanes) gave 430E(1.17 g, 75%) as a light yellow solid. It has a retention time of 6.96min (standard LC1 method, 8 min run). MS Found: (M+H)⁺=520.2

430F—Preparation of6-Amino-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine-3-carbonitrileHydrochloride

A suspension of 43E (600 mg, 1.15 mmol) and 10% Pd/C (120 mg, 20% wt) inMeOH (20 ml) was stirred at rt under H₂ balloon for 4 h. HCl was added(4 M in dioxane, 5 ml). The catalyst was filtered off through celite andthe filtrate was concentrated in vacuo to give the hydrochloride salt of430F (486 mg, 100%) as a yellow solid. It has a retention time of 4.91min (standard LC1 method, 8 min run). MS Found: (M+H)⁺=387.3

430—Preparation of3-Acetylamino-N-{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6yl}-benzamide

A solution of 430F (42 mg, 0.10 mmol), 3-acetylamino-benzoic acid (27mg, 0.15 mmol), PyBrop (73 mg, 0.15 mmol) and DIEA 70 μl, 0.40 mmol) inDMF (1 ml) was stirred at room temperature for 16 h under argon. Treatedwith EtOAc (30 ml), the mixture was washed with H₂O (3×10 ml) and brine(10 ml), dried with Na₂SO₄. Removal of the solvent followed by flashchromatography of the residue on silica gel (50% EtOAc-CH₂Cl₂) gave 430(38 mg, 70%) as a light yellow solid. It has a retention time of 6.16min (standard LC1 method, 8 min run). MS Found: (M+H)⁺=547.2

EXAMPLE 431

3-Acetylamino-N-{3-cyano-4-[5-(2-methoxy-phenoxy)-pyridin-2-ylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-benzamide

The title compound (27.3 mg, 50%) was prepared from the hydrochloridesalt of 430F (42 mg, 0.10 mmol) and 4-acetylamino-benzoic acid (27 mg,0.15 mmol) by a route analogous to that used for the preparation ofcompound 430. It is a slight yellow solid and has a retention time of6.14 min (standard LC1 method, 8 min run). MS Found: (M+H)⁺=547.1

EXAMPLE 432

{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-methyl-carbamicAcid 2-Morpholin-4-yl-ethyl Ester 432A—Preparation of{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicAcid 2-Morpholin-4-yl-ethyl Ester

A mixture of 430D (41 mg, 0.10 mmol), Et₃N (56 μl, 0.40 mmol) and DPPA(43 μl, 0.20 mmol) in dioxane (1 ml) was stirred at rt for 2 h underargon, 2-morpholin-4-yl-ethanol (49 μl, 0.40 mmol) was added. Theresulting mixture was heated to 80° C. for 2 h, cooled to rt. Treatedwith EtOAc (20 ml), the mixture was washed with H₂O (2×5 ml) and brine(10 ml), dried with Na₂SO₄. Removal of the solvent followed by flashchromatography of the residue on silica gel (3%-5% MeOH—CH₂Cl₂) gave432A (47 mg, 88%) as a light yellow solid. It has a retention time of5.35 min (∠Cl, 8 min. run). MS Found: (M+H)⁺=543.2

432—Preparation of{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-methyl-carbamicAcid 2-Morpholin-4-yl-ethyl Ester

To a mixture of 432A (27 mg, 0.050 mmol) and CH₃I (3.1 μl, 0.05 mmol) inTHF (1 ml) was added NaH (1.5 mg, 0.06 mmol). The resulting mixture wasstirred at rt for 2 h under argon. A drop of EtOH was added to quenchthe reaction. Removal of the solvent under reduced pressure followed byflash chromatography of the residue on silica gel (5/30/65MeOH/EtOAc/CH₂Cl₂) gave 432 (17.1 mg, 62%) as a yellow oil. It has aretention time of 5.70 min (standard LC1 method, 8 min run). MS Found:(M+H)⁺=557.1

EXAMPLE 433

[3-Cyano-4-(4-{2-[1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-carbamicAcid 2-Morpholin-4-yl-ethyl Ester 433A—Preparation of2-Methyl-2-[2-(4-nitro-phenoxy)-phenoxy]-propionic Acid Methyl Ester

Compound 433A (5.63 g, 98%) was prepared from 1A (4.00 g, 17.3 mmol) andmethyl 2-hydroxyisobutyrate (5.00 ml, 43.3 mmol) by a route analogous tothat used for the preparation of compound 388B. It is a faintly yellowsolid.

433B—Preparation of 2-Methyl-2-[2-(4-nitro-phenoxy)-phenoxy]-propionicAcid

To a solution of 433A (5.05 g, 15.2 mmol) in a mixed solvent of THF/MeOH(45 ml, 2/1) was added 2N NaOH (15.2 ml, 30.4 mmol). The mixture wasstirred at rt for 2.5 h, concentrated. The residue was purified by flashchromatography on silica gel (2%-5% MeOH—CH₂Cl₂) gave 433B (4.38 g, 91%)as a light yellow solid.

433C—Preparation ofN-(2-Hydroxy-ethyl)-2-methyl-2-[2-(4-nitro-phenoxy)-phenoxy]-propionamide

To a solution of 433B (714 mg, 2.25 mmol) in dry CH₂Cl₂ (10 ml) wasadded (COCl)₂ (295 μl, 3.38 mmol) followed by anhydrous DMF (17.4 μl,0.225). The mixture was stirred at rt for 3 h, concentrated in vacuo togive the acid chloride intermediate.

To a solution of the acid chloride in dry CH₂Cl₂ (4 ml) at 0° C. underargon was added a solution of ethanolamine (163 μl, 2.70 mmol) and DIEA(589 μl, 3.38 mmol) in dry CH₂Cl₂ (4 ml). The mixture was stirred at rtfor 1.25 h. Treated with EtOAc (80 ml), the mixture was washed with 1NHCl (120 ml), saturated NaHCO₃ (120 ml), brine and dried with Na₂SO₄.Removal of solvent under reduce pressure followed by flashchromatography on silica gel (10%-40% EtOAc—CH₂Cl₂) gave 433C (794 mg,98%) as a faintly amber viscous oil. MS Found: (M+H)⁺=361.0

433D—Preparation of2-[2-(4-Amino-phenoxy)-phenoxy]-N-(2-hydroxy-ethyl)-2-methyl-propionamide

A mixture of 433C (310 mg, 0.860 mmol) and 10% Pd/C (62.0 mg, 20 wt %)in MeOH (5 ml) was stirred vigorously under balloon of H₂ for 1 h.Filtered through Celite followed by 0.45μ syringe filter, the filtratewas concentrated to give 46D (252 mg, 89%) as a faintly amber resin. MSFound: (M+H)⁺=331.1

433E—Preparation of3-Cyano-4-(4-{2-[1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Ethyl Ester

Compound 433E (146 mg, 83%) was prepared from4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acidethyl ester (Example 1D) (126 mg, 0.476 mmol) and 433D (165 mg, 0.500mmol) by a route analogous to that used for the preparation of compound388D. It is a cream-colored crystalline solid. LCMS Found: (M+H)⁺=558.1

433F—Preparation of3-Cyano-4-(4-{2-[1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid

A mixture of 433E (180 mg, 0.323 mmol) and 1N NaOH (0.68 ml, 0.68 mmol)in EtOH (4 ml) was heated to reflux for 2 days, cooled to rt. Removal ofthe solvent in vacuo gave a gray oil. Treated with H₂O (4 ml), theaqueous solution was washed with EtOAc (3×2 ml) and added to a mixtureof 6N HCl (1.5 ml) and brine (5 ml). The resulting suspension was cooledto 0° C. and filtered, dried in vacuo to gave 433F (171 mg, 96%) as adim dark solid. It has a retention time of 5.31 min (standard LC1method, 8 min run). MS Found: (M+H)⁺=530.0

433G—Preparation of4-[4-(2-{1-[2-(Tert-butyl-dimethyl-silanyloxy)-ethylcarbamoyl]-1-methyl-ethoxy}-phenoxy)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid

A solution of 433F (164 mg, 0.31 mmol), DIEA (0.27 ml, 1.55 mmol), DMAP(7.6 mg, 0.062 mmol) and TBSCl (140 mg, 0.93 mmol) in THF (4 ml) wasstirred under argon at rt for 2 h. 1N NaOH (0.70 ml, 0.70 mmol) wasadded. The resulting mixture was stirred at rt for 1 h. Removal of thesolvent followed by flash chromatography of the residue of silica gel(2%-5% MeOH—CH₂Cl₂) gave 433G (75 mg, 38%) as a yellow oil. It has aretention time of 7.43 min (standard LC1 method, 8 min run). MS Found:(M+H)⁺=644.0

433H—Preparation of{4-[4-(2-{1-[2-(Tert-butyl-dimethyl-silanyloxy)-ethylcarbamoyl]-1-methyl-ethoxy}-phenoxy)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-d]pyridazin-6-yl}-carbamicAcid 2-Morpholin-4-yl-ethyl Ester

Compound 433H (28 mg, 67%) was prepared from 433G (35 mg, 0.054 mmol)and 2-morpholin-4-yl-ethanol (26 μl, 0.22 mmol) by a route analogous tothat used for the preparation of compound 433A. It is a light yellow oiland has a retention time of 7.06 min (standard LC1 method, 8 min run).MS Found: (M+H)⁺=772.3

433—Preparation of[3-Cyano-4-(4-{2-[1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-carbamicAcid 2-Morpholin-4-yl-ethyl Ester

To a solution of 433H (18 mg, 0.023 mmol) in CH₃CN (0.5 ml) was addedHF.Pyr (70% wt/wt) (50 μl). The mixture was stirred at rt for 0.5 h.Saturated NaHCO₃ (2 ml) was added, saturated with solid Na₂SO₄. Themixture was extracted with EtOAc (3×5 ml). Removal of the solvent of thecombined organic layers followed by flash chromatography of the residueon silica gel (1%-3% MeOH—CH₂Cl₂) gave 433 (15 mg, 98%) as a lightyellow oil. It has a retention time of 4.89 min (standard LC1 method, 8min run). MS Found: (M+H)⁺=658.2.

EXAMPLE 434

VEGFR-2 and FGFR-1 Kinase assays Reagents Final Concentration StockSolution VEGFR-2 FGFR-1 Tris pH 7.0  20 mM  20 mM BSA 10 mg/ml 25 μg/ml25 □g/ml MnCl₂ (1 M) 1.5 mM 0.5 mM MgCl₂ (1 M) — 0.5 mM DTT(1 M) 0.5 mM0.5 mM Enzyme Stock in 10% glycerol (1 mg/ml) 5 ng/rxn 20 ng/rxnPolyglu/tyr (10 mg/ml) 80 μg/ml 30 □g/ml ATP (1 mM) 2.5 μM 1.0 μM γ-ATP(10 μCi/μl) 0.5 μCi/ml 0.5 μCi

Incubation mixtures employed for VEGFR-2 or FGFR-1 assay contained thesynthetic substrate polyGlu:Tyr, (4:1), ATP, ATP-γ-³³P and buffercontaining Mn⁺⁺ and/or Mg⁺⁺, dithiothreitol (DTT), bovine serum albumin(BSA), and Tris buffer. The reaction was initiated by addition of enzymeand after 60 minutes was terminated by the addition of trichloroaceticacid (TCA) to a concentration of 30% on a volume percent basis.Inhibitors in accordance with the invention were brought to aconcentration of 10 mM in DMSO. Assays were prepared in a 96 wellformat. Compounds were diluted 1:500 in DMSO and then 1:10 in water fora final DMSO concentration of 10%. Aliquots of 10 μL were added to rowsB-H in a 96 well format of 10% DMSO. Aliquots of 20 μl of inhibitorsolution were added to row A at a concentration 5 fold higher thanrunning conditions. A 10 μL aliquot was transferred to each row with 10pipetting phases for mixing, and at row F a 10 μL aliquot was discarded.Row G was a control with no compound and row H was a no-compound andno-enzyme control. Enzyme and substrate were delivered using a TomtecQuadra station.

Plates were covered with sticky plate tops, incubated at 27° C. for 60minutes, and then acid precipitated with TCA for 20 minutes on ice. Theprecipitate was transferred to UniFilter-96, GF/C microplates usingeither a Tomtec or Packard FilterMate harvester. Activity was determinedby quantifying the incorporated radioactivity using a Packard TopCountMicroplate Scintillation Counter following the addition of Microscint-20cocktail into each dried well of the UniFilter microplates.

Tested compounds of formula I inhibited VEGFR-2 and FGFR-1 kinases withIC₅₀ values ≦80 μM.

EXAMPLE 435 HER1, HER2 or HER4 Kinase Assays

Compounds of interest were assayed in a kinase buffer that contained 20mM Tris.HCl, pH 7.5, 10 mM MnCl₂, 0.5 mM dithiothreitol, bovine serumalbumin at 0.1 mg/ml, poly(glu/tyr, 4:1) at 0.1 mg/ml, 1□M ATP, and4□Ci/ml [□-³³P]ATP. Poly(glu/tyr, 4:1) is a synthetic polymer thatserves as a phosphoryl acceptor and is purchased from Sigma Chemicals.The kinase reaction is initiated by the addition of enzyme and thereaction mixtures were incubated at 26° C. for 1 h. The reaction isterminated by the addition of EDTA to 50 mM and proteins areprecipitated by the addition of trichloroacetic acid to 5%. Theprecipitated proteins are recovered by filtration onto Packard Unifilterplates and the amount of radioactivity incorporated is measured in aTopcount scintillation counter.

For the preparation of recombinant HER1 and HER4, the cytoplasmicsequences of the receptors were expressed in insect cells as GST fusionproteins, which were purified by affinity chromatography. Thecytoplasmic sequence of HER2 was subcloned into the baculovirusexpression vector pBlueBac4 (Invitrogen) and was expressed as anuntagged protein in insect cells. The recombinant protein was partiallypurified by ion-exchange chromatography.

The instant compounds inhibit HER1, HER2, and HER4 kinases with IC50values between 0.001 25 μM. Preferred compounds have IC₅₀ values between0.001-5.0 μM. More preferred compounds have IC₅₀ values between0.001-1.0 μM. Most preferred compounds have IC₅₀ values between0.001-0.1 μM.

A HERG potassium channel assay may be used to screen compounds for HERGactivity (see Caballero R, et al., “Direct Effects of Candesartan andEprosartan on Human Cloned Potassium Channels Involved in CardiacRepolarization,” Molecular Pharmacology, 59(4), 825-36, (2001)).Accordingly, preferred compounds have lower HERG assay activity.

For the preparation of recombinant HER1, the cytoplasmic sequences ofthe receptor were expressed in insect cells as a GST fusion protein,which was purified by affinity chromatography. The cytoplasmic sequenceof HER2 was subcloned into the baculovirus expression vector pBlueBac4(Invitrogen) and was expressed as an untagged protein in insect cells.The recombinant protein was partially purified by ion-exchangechromatography.

Tested compounds of formula I inhibited HER-1 and HER-2 kinases withIC50 values ≦100 μM.

EXAMPLE 436 MEK-ERK Kinase Cascade Assay

An in vitro 96-well plate assay described in Example 388, above, wasadopted with several modifications. Each well contained 30 □1 assaybuffer (Tris-HCl, pH 7.5, MgCl₂, DTT, BSA, Myelin basic protein (MBP),ATP and [□-³³P]ATP), 10 □1 inhibitor dilutions or empty DMSO solvent and10 □l enzyme mixture (5-10 ng MEK-EE and 100-200 ng ERK). The finalconcentrations in the assay were 20 mM Tris-HCl, pH 7.5, 10 mM MgCl₂,0.3 mM DTT, 50 □g Myelin basic protein (MBP), 10 □M ATP and 200nCi[□-³³P]ATP. The plates were incubated at room temperature for 60 minand reactions were terminated by the addition of 10 □l stop mixturecontaining 300 mM EDTA and 25 □g BSA. The samples were subjected toprecipitation with TCA containing ATP (final concentrations: TCA, 3.2%and ATP, 2.3 mM). The samples were transferred to a Packard GF/C 96-wellUnifilter plates using a Packard Filter Mate 196 Harvester. Followingdrying under light, the radioactivity of the residue in the wells wascounted with a Packard Top Count microplate counter.

Since this assay is a cascade assay, inhibitors of both MEK and ERK areexpected to be identified. Further in vitro analysis is required todetermine whether the “hits” were attributable to the inhibition of MEK(using MEK and kinase deficient ERK) or ERK (using activated ERK andMBP) inhibitors. Nevertheless, tested compounds of formula I inhibitedMEK and/or ERK with IC₅₀ values ≦10 μM.

EXAMPLE 437 Generation of p38 Kinases

cDNAs of human p38α, β and γ isozymes were cloned by PCR. These cDNAswere subcloned in the pGEX expression vector (Pharmacia). GST-p38 fusionprotein was expressed in E. coli and purified from bacterial pellets byaffinity chromatography using glutathione agarose. p38 fusion proteinwas activated by incubating with constitutively active MKK6. Active p38was separated from MKK6 by affinity chromatography. Constitutivelyactive MKK6 was generated according to Raingeaud et al. [Mol. Cell.Biol., 1247-1255 (1996)].

EXAMPLE 438 TNF-α Production by LPS-Stimulated PBMCs

Heparinized human whole blood was obtained from healthy volunteers.Peripheral blood mononuclear cells (PBMCs) were purified from humanwhole blood by Ficoll-Hypaque density gradient centrifugation andresuspended at a concentration of 5×10⁶/ml in assay medium (RPMI mediumcontaining 10% fetal bovine serum). 50 ul of cell suspension wasincubated with 50 ul of test compound (4× concentration in assay mediumcontaining 0.2% DMSO) in 96-well tissue culture plates for 5 minutes atRT. 100 ul of LPS (200 ng/ml stock) was then added to the cellsuspension and the plate was incubated for 6 hours at 37° C. Followingincubation, the culture medium was collected and stored at −20° C. TNF-αconcentration in the medium was quantified using a standard ELISA kit(Pharmingen—San Diego, Calif.). Concentrations of TNF-α and IC₅₀ valuesfor test compounds (concentration of compound that inhibitedLPS-stimulated TNF-α production by 50%) were calculated by linearregression analysis.

EXAMPLE 439 p38 Assay

The assays were performed in V-bottomed 96-well plates. The final assayvolume was 60 μl prepared from three 20 μl additions of enzyme,substrates (MBP and ATP) and test compounds in assay buffer (50 mM TrispH 7.5, 10 mM MgCl₂, 50 mM NaCl and 1 mM DTT). Bacterially expressed,activated p38 was pre-incubated with test compounds for 10 min. prior toinitiation of reaction with substrates. The reaction was incubated at25° C. for 45 min. and terminated by adding 5 μl of 0.5 M EDTA to eachsample. The reaction mixture was aspirated onto a pre-wet filtermatusing a Skatron Micro96 Cell Harvester (Skatron, Inc.), then washed withPBS. The filtermat was then dried in a microwave oven for 1 min.,treated with MeltilLex A scintillation wax (Wallac), and counted on aMicrobeta scintillation counter Model 1450 (Wallac). Inhibition datawere analyzed by nonlinear least-squares regression using Prizm(GraphPadSoftware). The final concentration of reagents in the assaysare ATP, 1 μM; [γ-³³P]ATP, 3 nM,; MBP (Sigma, #M1891), 2 μg/well; p38,10 nM; and DMSO, 0.3%.

EXAMPLE 440 TNF-α Production by LPS-Stimulated Mice

Mice (Balb/c female, 6-8 weeks of age, Harlan Labs; n=8/treatment group)were injected intraperitoneally with 50 ug/kg lipopolysaccharide (LPS; Ecoli strain 0111:B4, Sigma) suspended in sterile saline. Ninety minuteslater, mice were sedated by CO₂:O₂ inhalation and a blood sample wasobtained. Serum was separated and analyzed for TNF-alpha concentrationsby commercial ELISA assay per the manufacturer's instructions (R&DSystems, Minneapolis, Mn.).

EXAMPLE 441N-{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-methanesulfonylamino-benzamide

A mixture of6-amino-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine-3-carbonitrile(21 mg, 0.05 mmol), 3-methanesulfonylamino-benzoic acid (16 mg, 0.075mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (36 mg,0.075 mmol) and diisopropylethyl amine (35 □L, 0.20 mmol) were stirredin 1 ml of DMF at room temperature for 10 h, followed by an additional16 h of stirring at 60° C. The mixture was allowed to cool by to roomtemperature where upon it was treated with 50 ml of EtOAc. The mixturewas washed with water, (3×10 ml), followed by brine (5 ml) and thendried over Na₂SO₄. The solvent was removed in vacuo, and the resultingresidue was purified by silica gel chromatography using 20-30% gradientof EtOAc in dichoromethane to give 22.0 mg of compound XX as a lightyellow solid. Retention Time: 6.56 min. (Princeton chromatography HTScolumn, 5 micron, 4.6×50 mm, eluting with 5-100% of acetonitrile inwater over 8 minutes containing 0.1% TFA, 1.2 mL/min, monitoring at 215nm.).

EXAMPLES 442 TO 542

Further compounds of the present invention were prepared by proceduresanalogous to those described above and are listed in Table 2. Thechromatography techniques used to determine the retention times of thecompounds listed in Table 2 are as follows:

-   -   LC1=Princeton chromatography HTS column, 5 micron, 4.6×50 mm,        eluting with 5-100% of acetonitrile in water over 8 minutes        containing 0.1% TFA, 1.2 mL/min, monitoring at 215 nm.    -   LCMS1=Princeton chromatography HTS column, 5 micron, 3.0×5.0 mm,        eluting with 25-100% of acetonitrile in water over 2 minutes        containing 0.1% TFA then 100% acetonitrile for 0.25 minutes, 1.2        mL/min, monitoring by electrospray mass spectroscopy.    -   LCMS2=Princeton chromatography HTS column, 5 micron, 3.0×50 mm,        eluting with 10-100% of acetonitrile in water over 4 minutes        containing 0.1% formic acid then 100% acetonitrile for 0.25        minutes, 1.2 mL/min, monitoring by electrospray mass        spectroscopy.    -   MS method—ES positive        -   Analysis in ESI mode with SIR monitoring        -   Source            -   Capillary: 3.0 kV            -   Cone: 25 V            -   Source Block Temp: 150°            -   Desolvation Temp: 300°        -   MS            -   Ion energy: 0.5 V            -   LM resolution: 15.0            -   HM resolution: 15.0            -   Multiplier: 650            -   Cone gas flow: 110 l/h

The molecular mass of the compounds listed in Table 1 were determined byMS (ES) by the formula m/z

TABLE 2 Compound Structure Compound Name 442

5-Methyl-6-morpholin-4-ylmethyl-4- (4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3- carbonitrile 443

1-{3-Cyano-4-[2-fluoro-4-(thiazol-2- yloxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- (2-morpholin-4-yl-ethyl)-urea 444

3-Cyano-4-(4-{2-[1-(2-hydroxy- ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl- pyrrolo [1,2-b]pyridazine-6-carboxylicacid ethyl ester 445

{4-[3-Chloro-4-(1-methyl-1H- imidazol-2-ylsulfanyl)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b] pyridazin-6-yl}-carbamic acid 2-morpholin-4-yl-ethyl ester 446

3-Cyano-4-(4-phenoxy- phenylamino)-pyrrolo[1,2- b]pyridazin-6-carboxylicacid 447

{3-Cyano-4-[2-fluoro-4-(thiazol-2- yloxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-car- bamic acid 2-morpholin-4-yl-ethylester 448

3-Cyano-5-methyl-4-(2-methyl-4- phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 449

3-Cyano-4-(2-fluoro-4-phenoxy- phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 450

3-Cyano-4-(4-{2-[1-(2-hydroxy- ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl- pyrrolo[1,2-b]pyridazin-6- carboxylicacid ethyl ester 451

3-Cyano-4-(4-phenoxy- phenylamino)-pyrrolo[1,2-b]pyridazine-7-carboxylic acid 452

4-[3-Chloro-4-(1-methyl-1H- imidazol-2-ylsulfanyl)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b] pyridazine-6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide 453

4-(5-Bromo-pyridin-2-ylamino)-3- cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester 454

[3-Cyano-4-(4-{2-[1-(2-hydroxy- ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl- pyrrolo[1,2-b]pyridazin-6- yl]-carbamicacid 2- morpholin-4-yl-ethyl ester 455

3-Cyano-4-(4-hydroxy- cyclohexylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid ethyl ester 456

4-(7-Aza-bicyclo[2.2.1]hept-7-yl)-3- cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 457

4-(4-tert-Butoxycarbonyl-piperazin- 1-yl)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 458

3-Cyano-5-methyl-4-piperazin-1-yl- pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 459

4-(4-Benzoyl-piperazin-1-yl)-3- cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 460

4-(1-tert-Butoxycarbonyl-piperidin-4- ylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxy- lic acid ethyl ester 461

3-Cyano-4-(4-methanesulfonyl)- piperazin-1-yl)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 462

3-Cyano-5-methyl-4-(piperidin-4- ylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 463

4-(1-Acetyl-piperidin-4-ylamino)-3- cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 464

6-Formyl-7-iodo-5-methyl-4-(4- phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile 465

[3-Cyano-5-methyl-4-(4-phenoxy- phenylamino)-pyrrolo[1,2-b]pyridazin-6-yl]-carbamic acid 4- methanesulfonyl-butyl ester 466

3-Cyano-4-(4-{3-[1-(2-hydroxy- ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl- pyrrolo[1,2-b]pyridazine-6- carboxylicacid ethyl ester 467

[3-Cyano-4-(4-{3-[1-(2-hydroxy- ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl- pyrrolo [1,2-b]pyridazin-6-yl]-carbamicacid 2-morpholin-4-yl-ethyl ester 468

4-{4-[2-(1-tert-Butoxycarbonyl-1- methyl-ethoxy)-phenoxy]-phenylamino}-3-cyano-5-methyl- pyrrolo[1,2- b]pyridazine-6-carboxylicacid methyl ester 469

4-{4-[2-(1-Carboxy-1-methyl- ethoxy)-phenoxy]-phenylamino}-3-cyano-5-methyl-pyrrolo[1,2- b]pyridazine- 6-carboxylic acid methyl ester470

471

472

473

3-Acetylamino-N-[3-cyano-4-(4-{3- [1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenyl- amino)-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-benzamide 474

3-Cyano-4-(4-{2-[1- (ethylcarbamoylmethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}- phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid methyl ester 475

3-Cyano-4-(4-{2-[1- (ethoxycarbonylmethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}- phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid methyl ester 476

3-Cyano-5-methyl-4-[4-phenoxy-3- (2,2,2-trifluoro-acetoxymethyl)-phenylamino]-pyrrolo[1,2- b]pyridazine-6- carboxylic acid ethyl ester477

5-Amino-3-cyano-4-(4-phenoxy- phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 478

4-(4-{2-[1-(tert- Butoxycarbonylmethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}- phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid methyl ester 479

6-Hydroxy-5-methoxy-4-(4-phenoxy- phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile 480

7-Chloro-3-cyano-5-methyl-4-(4- phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester 481

7-Bromo-3-cyano-5-methyl-4-(4- phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester 482

3-Cyano-4-{4-[2-(2,3-dihydroxy- propoxy)-phenoxy]-phenylamino}-5-methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid methyl ester 483

3-Cyano-5-methyl-4-(4-phenoxy- benzoylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylic acid methyl ester 484

3-Cyano-5-methyl-4-(4-phenoxy- benzenesulfonylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 485

6-{3-[2-(1,1-Dioxo-116- thiomorpholin-4-yl)-ethyl]-2-oxo-imidazoline-1-carbonyl}-5-methyl- 4-(4-phenoxy-phenylamino)-pyrrolo[1,2- b]pyridazine-3-carbonitrile 486

3-Cyano-5-methyl-4-[4-(pyridin-2- yloxy)-phenylamino]-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 487

3-Cyano-5-methyl-4-[4-(pyridin-4- yloxy)-phenylamino]-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 488

3-Cyano-5-methyl-4-[4-(pyridin-3- yloxy)-phenylamino]-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 489

4-Acetylamino-N-{3-cyano-4-[4-(3- methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin- 6-yl}-benzamide 490

3-Acetylamino-N-{3-cyano-4-[4-(3- methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin- 6-yl}-benzamide 491

N-{3-Cyano-4-[4-(2-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- dimethyl- amino-benzamide 492

N-{3-Cyano-4-[4-(3-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- dimethyl- amino-benzamide 493

1H-Benzoimidazole-5-carboxylic acid {3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl- pyrrolo [1,2-b]pyridazin-6-yl}-amide 494

1H-Benzoimidazole-5-carboxylic acid {3-cyano-4-[4-(3-methoxy-phenoxy)-phenylamino]-5-methyl- pyrrolo [1,2-b]pyridazin-6-yl}-amide 495

3-Cyano-4-(4-{2-[1- (ethylcarbamoylmethyl-carbamoyl)-1-methyl-ethoxy]-phenyoxy}- phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid methyl ester 496

4-Benzenesulfonyl-3-cyano-5- methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 497

6-Isopropenyl-5-methyl-4-(4- phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile 498

3-[3-Cyano-5-methyl-4-(4-phenoxy- phenylamino)-pyrrolo[1,2-b]pyridazin-6-yloxy]-propane-1- sulfonic acid 499

(3-Morpholin-4-yl-propyl)-carbamic acid 3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b] pyridazin-6-yl ester 500

5-Methyl-4-(4-phenoxy- phenylamino)-6-pyridin-2-yl-pyrrolo[1,2-b]pyridazine-3- carbonitrile 501

3-Cyano-5-methoxy-4-(4-phenoxy- phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylic acid 502

(2-Morpholin-4-yl-ethyl)-carbamic acid 3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b] pyridazin-6-yl ester 503

(2-Morpholin-4-yl-ethyl)-carbamic acid 3-cyano-5-methoxy-4-(4-phenoxy-phenylamino)-pyrrolo[1,2- b]pyridazin-6-yl ester 504

3-[3-Cyano-5-methyl-4-(4-phenoxy- phenylamino)-pyrrolo[1,2-b]pyridazin-6-yloxycarbonylamino]- propionic acid 505

6-(3H-imidazol-4-yl)-5-methyl-4-(4- phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile 506

Furan-2-carboxylic acid {3-cyano-4- [4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2- b]pyridazin-6-yl}-amide 507

Thiophene-2-carboxylic acid {3- cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2- b]pyridazin-6-yl}-amide 508

3-Cyano-4-{4-[2-(3-hydroxy-2,3-bis- hydroxymethyl-propoxy)-phenoxy]-phenylamino}-5-methyl-pyrrolo[1,2- b]pyridazine-6-carboxylic acid methylester 509

N-{3-Cyano-4-[4-(2-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-4- morpholin- 4-yl-benzamide 510

N-{3-Cyano-4-[4-(2-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-2- methane- sulfonyl-benzamide 511

2-Oxo-imidazolidine-1-carboxylic acid {3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl- pyrrolo [1,2-b]pyridazin-6-yl}-amide 512

Benzo[1,2,5]thiadiazole-5-carboxylic acid {3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl- pyrrolo[1,2-b]pyridazin-6-yl}-amide 513

5-Methanesulfonyl-thiophene-2- carboxylic acid {3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5- methyl- pyrrolo[1,2-b]pyridazin-6-yl}-amide 514

3-Chloro-4-methanesulfonyl- thiophene-2-carboxylic acid {3-cyano-4-[4-(2-methoxy-phenoxy)- phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin- 6-yl}-amide 515

[1,2,3]Thiadiazole-4-carboxylic acid {3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo [1,2-b]pyridazin-6-yl}-amide 516

3,5-Bis-acetylamino-N-{3-cyano-4- [4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2- b]pyridazin- 6-yl}-benzamide 517

N-{3-Cyano-4-[4-(2-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-4- guanidino- benzamide; trifluoro-aceticacid salt 518

N-{3-Cyano-4-[4-(3-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- nitro-benzamide 519

N-{3-Cyano-4-[4-(3-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-4- nitro-benzamide 520

N-{3-Cyano-4-[4-(2-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- guanidino-benzamide; trifluoro-aceticacid salt 521

3-Amino-N-{3-cyano-4-[4-(3- methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6- yl}-benzamide 522

N-{3-Cyano-4-[4-(3-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- ureidobenzamide 523

N-{3-Cyano-4-[4-(3-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-4- guanidinobenzamide 524

N-{3-Cyano-4-[4-(3-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- ureidobenzamide, trifluoro-acetic acidsalt 525

N-{3-Cyano-4-[4-(3-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-4- guanidinobenzamide, trifluoro-aceticacid salt 526

3,4-Bis-acetylamino-N-{3-cyano-4- [4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2- b]pyridazin-6-yl}-benzamide 527

2-Oxo-2,3-dihydro-1H-indole-6- carboxylic acid {3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5- methyl-pyrrolo[1,2-b]-pyridazin-6-yl}-amide 528

2-Oxo-2,3-dihydro-1H- benzoimidazole-5-carboxylic acid {3-cyano-4-[4-(2-methoxy-phenoxy)- phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin- 6-yl}-amide 529

2,3-Dioxo-1,2,3,4-tetrahydro- quinoxaline-6-carboxylic acid {3-cyano-4-[4-(2-methoxy-phenoxy)- phenylamino]- 5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide 530

Thiophene-2-carboxylic acid {3- cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2- b]pyridazin-6-yl}-amide 531

1H-imidazole-2-carboxylic acid [3- cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin- 6-yl]-amide 532

5-Methyl-4-(4-phenoxy- phenylamino)-7-phenyl-pyrrolo[1,2-b]pyridazine-3-carbonitrile 533

4-[4-(2-Methoxy-phenoxy)- phenylamino]-5-methyl-6-(pyrimidin-2-ylamino)-pyrrolo[1,2- b]pyridazine-3- carbonitrile 534

N-{3-Cyano-4-[4-(2-methoxy- phenyoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}- guanidine; trifluoro-acetic acid salt 535

4-[4-(2-Methoxy-phenoxy)- phenylamino]-5-methyl-6-(pyridin-2-ylamino)-pyrrolo[1,2-b]pyridazine-3- carbonitrile 536

6-(Di-pyrazin-2-yl-amino)-4-[4-(2- methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine- 3-carbonitrile 537

4-[4-(2-Methoxy-phenoxy)- phenylamino]-5-methyl-6-(pyrazin-2-ylamino)-pyrrolo[1,2-b]pyridazine-3- carbonitrile 538

Acetic acid (3-{3-cyano-4-[4-(2- methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl- carbamoyl}-phenylcarbamoyl)- methylester 539

N-{3-Cyano-4-[4-(2-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3- nitro-benzamide 540

4-(1-Benzoyl-piperidin-4-ylamino)-3- cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 541

4-(4-Acetyl-piperazin-1-yl)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6- carboxylic acid ethyl ester 542

N-{3-Cyano-4-[4-(2-methoxy- phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-(3- ethyl- ureido)-benzamide

EXAMPLE 5433-Cyano-5,7-dimethyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Ethyl Ester

LCMS4: 97.5% at 2.05 min (retention time) (PrinctonSPHER HTS 60A5Ucolumn, 50×3.0 mm, part# 050030-1570, eluting with 25-100% aqueousacetonitrile containing 0.1% trifluoroacetic acid, 1.5 mL/min. It rampsto 100% acetonitrile at 2.2 min and holds till 3.2 min. Collectionstopped at 3.4 min). MS (ELS): m/z 427.1 [M+H]⁺.

EXAMPLE 5447-Chloro-3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Methyl Ester

LCMS5: 100% at 1.65 min (retention time) (Phenomenex Luna C-8 columns 5um, 3×50 mm, eluting with 25-100% aqueous acetonitrile containing 0.1%formic acid and 0.01% trifluoroacetic acid, 6.0 mL/min. It ramps to 100%acetonitrile at 1.8 min and holds till 2.25 min. Collection stopped at2.35 min). MS (ELS): m/z 433.1 [M+H]⁺.

Structure was also confirmed by X-ray crystallography.

EXAMPLE 5457-Bromo-3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Methyl Ester

LCMS5: 100% at 1.68 min (retention time) (Phenomenex Luna C-8 columns 5um, 3×50 mm, eluting with 25-100% aqueous acetonitrile containing 0.1%formic acid and 0.01% trifluoroacetic acid, 6.0 mL/min. It ramps to 100%acetonitrile at 1.8 min and holds till 2.25 min. Collection stopped at2.35 min). MS (ELS): m/z 477.1 [M+H]⁺.

EXAMPLE 5463-Cyano-4-{4-[2-(2,3-dihydroxy-propoxy)-phenoxy]-phenylamino}-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Methyl Ester

LCMS3: 99.6% at 1.37 min (retention time) (PrinctonSPHER HTS 60A5Ucolumn, 50×3.0 mm, part# 050030-1570, eluting with 25-100% aqueousacetonitrile over 2.4 min containing 0.1% trifluoroacetic acid, 1.5mL/min. MS (ELS): m/z 489.3 [M+H]⁺.

EXAMPLE 5473-Cyano-4-{4-[2-(3-hydroxy-2,2-bis-hydroxymethyl-propoxy)-phenoxy]-phenylamino}-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Methyl Ester

LCMS3: 99.5% at 1.21 min (retention time) (PrinctonSPHER HTS 60A5Ucolumn, 50×3.0 mm, part# 050030-1570, eluting with 25-100% aqueousacetonitrile over 2.4 min containing 0.1% trifluoroacetic acid, 1.5mL/min. MS (ELS): m/z 533.3 [M+H]⁺.

EXAMPLE 5483-Cyano-4-{4-[2-(2-hydroxy-ethoxy)-phenoxy]-phenylamino}-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicAcid Methyl Ester

LCMS3: 99.8% at 1.60 min (retention time) (PrinctonSPHER HTS 60A5Ucolumn, 50×3.0 mm, part# 050030-1570, eluting with 25-100% aqueousacetonitrile over 2.4 min containing 0.1% trifluoroacetic acid, 1.5mL/min. MS (ELS): m/z 459.3 [M+H]⁺.

EXAMPLE 5493-Cyano-4-(4-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo]1,2-b]pyridazine-6-carboxylicAcid Methyl Ester

LCMS3: 99.8% at 1.70 min (retention time) (PrinctonSPHER HTS 60A5Ucolumn, 50×3.0 mm, part# 050030-1570, eluting with 25-100% aqueousacetonitrile over 2.4 min containing 0.1% trifluoroacetic acid, 1.5mL/min. MS (ELS): m/z 503.3 [M+H]⁺.

LCMS5:

-   -   Hardware        -   Leap Technologies PAL.HTS injector with 4-Channel Eluate LC            Valve System controlled by software        -   Waters 1525 Binary HPLC system controlled by software        -   Micromass ZQ Electrospray MS equipped with 4-channel-MUX            capabilities controlled by software        -   4 Sedere Sedex 75 ELS detectors controlled by contact            closure        -   Ticoscen, Inc. Gas AC Mizer 2000 which turns off ELS gases            controlled by contact closure        -   Phenomenex Luna C-8 columns 5 um, 3×50 mm        -   Alltech 2 um PEEK encased frits    -   LC Method

Time % Solv. A % Solv. B Flow 0.00 75.0 25.0 6.00 1.80 0.0 100.0 6.002.25 0.0 100.0 6.00 2.35 75.0 25.0 6.00 Solvent A = Water + 0.1% FormicAcid + 0.01% TFA Solvent B = Acetonitrile + 0.1% Formic Acid + 0.01% TFA

-   -   MS method—ES positive        -   Analysis in ESI mode with SIR monitoring        -   Source            -   Capillary: 3.0 kV            -   Cone: 25 V            -   Source Block Temp: 150°            -   Desolvation Temp: 300°        -   MS            -   Ion energy: 0.5 V            -   LM resolution: 15.0            -   HM resolution: 15.0            -   Multiplier: 650            -   Cone gas flow: 110 l/h

The entire disclosures of the publications cited above are incorporatedherein by reference. While certain preferred embodiments of the presentinvention have been described and specifically exemplified above, it isnot intended that the invention be limited to such embodiments. Variousmodifications may be made to the invention without departing from thescope and spirit thereof as set forth in the following claims.

1. A compound selected from the group consisting of3-Cyano-4-[4-(cyano-phenyl-methyl)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,2-[3-Cyano-6-ethoxycarbonyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-5-ylmethyl]-malonicacid diethyl ester,5-Methyl-4-(4-phenoxy-phenylamino)-6-phenylamino-pyrrolo[1,2-b]pyridazine-3-carbonitrile,3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid (2-amino-phenyl)-amide,6-(1H-Benzoimidazol-2-yl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,N-[3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-yl]-2-fluoro-benzamide,5-Methyl-6-(2-methyl-4-oxo-4H-quinazolin-3-yl)-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,6-Benzylamino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,N-[3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-yl]-benzenesulfonamide,6-[bis(phenylsulfonyl)amino]-5-methyl-4-[(4-phenoxyphenyl)amino]-7a-hydropyrrolo[1,2-e]pyridazine-3-carbonitrile,6-(Benzothiazol-2-ylamino)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,{4-[4-(6-Chloro-pyridazin-3-yloxy)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester,{3-Cyano-5-methyl-4-[4-(1-phenyl-1H-tetrazol-5-yloxy)-phenylamino]-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester,{3-Cyano-5-methyl-4-[4-(2-nitro-phenoxy)-phenylamino]-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester,{4-[4-(2-Amino-phenoxy)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester,{4-[4-(2-Acetylamino-phenoxy)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester,5-Methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,[4-(4-Bromo-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-carbamicacid 2-morpholin-4-yl-ethyl ester,{3-Cyano-4-[4-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-7-yloxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester,4-(4-{2-[1-(tert-Butoxycarbonylmethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,4-(4-{2-[1-(Carboxymethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,3-Cyano-4-(4-{2-[1-(ethylcarbamoylmethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,4-(1-Benzyl-piperidin-4-ylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,3-Cyano-5-methyl-4-(4-phenoxy-benzenesulfonyl)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethylester,3-Cyano-5-methoxy-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,3-Cyano-5-methyl-4-[4-phenoxy-3-(tetrahydro-pyran-2-yloxymethyl)-phenylamino]-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,3-Cyano-4-(3-hydroxymethyl-4-phenoxy-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,6-(1-Hydroxy-1-methyl-ethyl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,Trifluoro-methanesulfonic acid3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-ylester,6-(1-Hydroxy-1methyl-ethyl)-5-methoxy-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,6-Hydroxy-5-methoxy-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,5,6-Dimethoxy-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,6-(4-Methoxy-phenyl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,5-Methyl-4-(4-phenoxy-phenylamino)-6-phenyl-pyrrolo[1,2-b]pyridazine-3-carbonitrile,3-Cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,7-Bromo-3-cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,7-Chloro-3-cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,3-Cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-7-carboxylicacid ethyl ester,7-Hydroxymethyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,3-Cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-7-carboxylicacid,3-Cyano-5,7-dimethyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,5-Methyl-6-(4-methyl-piperazin-1-ylmethyl)-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile[3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-ylmethoxy]-aceticacid ethylester,3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carbonyl-N-hydroxylacetamidine,6-(Hydroxyimino-methyl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,N-Benzyl-N-[3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-ylmethyl]-acetamide,N-[3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-yl]-methanesulfonamide,5-Methyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methoxy-methyl-amide,5-Methyl-4-(4-phenoxy-phenylamino)-6-propynoyl-pyrrolo[1,2-b]pyridazine-3-carbonitrile,3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carbonyl-N-hydroxymorpholinyl-acetamidine,5-Methyl-6-(3-morpholin-4-yl-[1,2,4]oxadiazol-5-yl)-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,6-(3-Methanesulfonylmethyl-[1,2,4]oxadiazol-5-yl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,3-(Imino-hydrazino-methyl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,5-Methyl-4-(4-phenoxy-phenylamino)-6-(4-phenyl-thiazol-2-yl)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,6-(4,5-Dihydro-1H-imidazol-2-ylamino)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,6-(2-Amino-4-hydroxy-4,5-dihydro-thiazol-4-ylamino)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ether ester,3-Cyano-4-[2-fluoro-4-(thiazol-2-yloxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,1-{4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-(2-morpholin-4-yl-ethyl)-urea,3-Cyano-5-methyl-4-(5-phenoxy-pyridin-2-ylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,3-Acetylamino-N-{3-cyano-4-[5-(2-methoxy-phenoxy)-pyridin-2-ylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-benzamide,3-Acetylamino-N-{3-cyano-4-[5-(2-methoxy-phenoxy)-pyridin-2-ylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-benzamide,{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-methyl-carbamicacid 2-morpholin-4-yl-ethyl ester,[3-Cyano-4-(4-{2-[1-(2-hydroxy-ethylcarbamoyl)-1-methoxy-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-carbamicacid 2-morpholin-4-yl-ethyl ester,N-{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-methanesulfonylamino-benzamide,5-Methyl-6-morpholin-4-ylmethyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,1-{3-Cyano-4-[2-fluoro-4-(thiazol-2-yloxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-(2-morpholin-4-yl-ethyl)-urea,3-Cyano-4-(4-{2-[1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,{4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester,3-Cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid,{3-Cyano-4-[2-fluoro-4-(thiazol-2-yloxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester,3-Cyano-5-methyl-4-(2-methyl-4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,3-Cyano-4-(2-fluoro-4-phenoxy-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,3-Cyano-4-(4-{2-[1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,3-Cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-7-carboxylicacid,4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid (2-morpholin-4-yl-ethyl)-amide,4-(5-Bromo-pyridin-2-ylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,[3-Cyano-4-(4-{2-[1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-carbamicacid 2-morpholin-4-yl-ethyl ester,3-Cyano-4-(4-hydroxy-cyclohexylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,4-(7-Aza-bicyclo[2.2.1]hept-7-yl)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,4-(4-tert-Butoxycarbonyl-piperazin-1-yl)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,3-Cyano-5-methyl-4-piperazin-1-yl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,4-(4-Benzoyl-piperazin-1-yl)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,4-(1-tert-Butoxycarbonyl-piperidin-4-ylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,3-Cyano-4-(4-methanesulfonyl-piperazin-1-yl)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,3-Cyano-5-methyl-4-(piperidin-4-ylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,4-(1-Acetyl-piperidin-4-ylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,6-Formyl-7-iodo-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,[3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-yl]-carbamicacid 4-methanesulfonyl-butyl ester,3-Cyano-4-(4-{3-[1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,[3-Cyano-4-(4-{3-[1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-carbamicacid 2-morpholin-4-yl-ethyl ester,4-{4-[2-(1-tert-Butoxycarbonyl-1-methyl-ethoxy)-phenoxy]-phenylamino}-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,4-{4-[2-(1-Carboxy-1-methyl-ethoxy)-phenoxy]-phenylamino}-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,3-Acetylamino-N-[3-cyano-4-(4-{3-[1-(2-hydroxy-ethylcarbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl]-benzamide,3-Cyano-4-(4-{2-[1-(ethylcarbamoylmethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,3-Cyano-4-(4-{2-[1-(ethoxycarbonylmethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,3-Cyano-5-methyl-4-[4-phenoxy-3-(2,2,2-trifluoro-acetoxymethyl)-phenylamino]-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,5-Amino-3-cyano-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,4-(4-{2-[1-(tert-Butoxycarbonylmethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,6-Hydroxy-5-methoxy-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,7-Chloro-3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,7-Bromo-3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,3-Cyano-4-{4-[2-(2,3-dihydroxy-propoxy)-phenoxy]-phenylamino}-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,3-Cyano-5-methyl-4-(4-phenoxy-benzoylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,3-Cyano-5-methyl-4-(4-phenoxy-benzenesulfonylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,6-{3-[2-(1,1-Dioxo-1l6-thiomorpholin-4-yl)-ethyl]-2-oxo-imidazoline-1-carbonyl]-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,3-Cyano-5-methyl-4-[4-(pyridin-2-yloxy)-phenylamino]-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,3-Cyano-5-methyl-4-[4-(pyridin-4-yloxy)-phenylamino]-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,3-Cyano-5-methyl-4-[4-(pyridin-3-yloxy)-phenylamino]-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,4-Acetylamino-N-{3-cyano-4-[4-(3-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-benzamide,3-Acetylamino-N-{3-cyano-4-[4-(3-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-benzamide,N-{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-dimethylamino-benzamide,N-{3-Cyano-4-[4-(3-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-dimethylamino-benzamide,1H-Benzoimidazole-5-carboxylic acid{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide,1H-Benzoimidazole-5-carboxylic acid{3-cyano-4-[4-(3-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide,3-Cyano-4-(4-{2-[1-(ethylcarbamoylmethyl-carbamoyl)-1-methyl-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,4-Benzenesulfonyl-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,6-Isopropenyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,3-[3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-yloxy]-propane-1-sulfonicacid, (3-Morpholin-4-yl-propyl)-carbamic acid3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-ylester,5-Methyl-4-(4-phenoxy-phenylamino)-6-pyridin-2-yl-pyrrolo[1,2-b]pyridazine-3-carbonitrile,3-Cyano-5-methoxy-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid, (2-Morpholin-4-yl-ethyl)-carbamic acid3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-ylester, (2-Morpholin-4-yl-ethyl)-carbamic acid3-cyano-5-methoxy-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-ylester,3-[3-Cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-yloxycarbonylamino]-propionicacid,6-(3H-Imidazol-4-yl)-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo]1,2-b]pyridazine-3-carbonitrile,Furan-2-carboxylic acid{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide,Thiophene-2-carboxylic acid{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide,3-Cyano-4-{4-[2-(3-hydroxy-2,2-bis-hydroxymethyl-propoxy)-phenoxy]-phenylamino}-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,N-{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-4-morpholin-4-yl-benzamide,N-{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-2-methanesulfonyl-benzamide,2-Oxo-imidazolidine-1-carboxylic acid{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide,Benzo[1,2,5]thiadiazole-5-carboxylic acid{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide,5-Methanesulfonyl-thiophene-2-carboxylic acid{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide3-Chloro-4-methanesulfonyl-thiophene-2-carboxylic acid{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide,[1,2,3Thiadiazole-4-carboxylic acid{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide,3,5-Bis-acetylamino-N-{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-d]pyridazin-6-yl}-benzamide,N-{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-4-guanidino-benzamide;trifluoro-acetic acid salt,N-{3-Cyano-4-[4-(3-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-nitro-benzamide,N-{3-Cyano-4-[4-(3-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-4-nitro-benzamide,N-{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-guanidino-benzamide;trifluoro-acetic acid salt,3-Amino-N-{3-cyano-4-[4-(3-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-benzamide,N-{3-Cyano-4-[4-(3-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-ureido-benzamide,N-{3-Cyano-4-[4-(3-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-4-guanidino-benzamide,N-{3-Cyano-4-[4-(3-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-ureido-benzamide,trifluoro-acetic acid salt,N-{3-Cyano-4-[4-(3-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-4-guanidino-benzamide,trifluoro-acetic acid salt,3,4-Bis-acetylamino-N-{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-benzamide,2-Oxo-2,3-dihydro-1H-indole-6-carboxylic acid{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide,2-Oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide,2,3-Dioxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide,Thiophene-2-carboxylic acid{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-amide,1H-Imidazole-2-carboxylic acid[3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazin-6-yl]-amide,5-Methyl-4-(4-phenoxy-phenylamino)-7-phenyl-pyrrolo[1,2-b]pyridazine-3-carbonitrile,4-[4-(2-Methoxy-phenoxy)-phenylamino]-5-methyl-6-(pyrimidin-2-ylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,N-{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-guanidine;trifluoro-acetic acid salt,4-[4-(2-Methoxy-phenoxy)-phenylamino]-5-methyl-6-(pyridin-2-ylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,6-(Di-pyrazin-2-yl-amino)-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine-3-carbonitrile,4-[4-(2-Methoxy-phenoxy)-phenylamino]-5-methyl-6-(pyrazin-2-ylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile,Acetic acid(3-{3-cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-ylcarbamoyl}-phenylcarbamoyl)-methylester,N-{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-nitro-benzamide,4-(1-Benzoyl-piperidin-4-ylamino)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,4-(4-Acetyl-piperazin-1-yl)-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,N-{3-Cyano-4-[4-(2-methoxy-phenoxy)-phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazin-6-yl}-3-(3-ethyl-ureido)-benzamide,3-Cyano-5,7-dimethyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid ethyl ester,7-Chloro-3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,7-Bromo-3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,3-Cyano-4-{4-[2-(2,3-dihydroxy-propoxy)-phenoxy]-phenylamino}-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,3-Cyano-4-{4-[2-(3-hydroxy-2,2-bis-hydroxymethyl-propoxy)-phenoxy]-phenylamino}-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester,3-Cyano-4-{4-[2-(2-hydroxy-ethoxy)phenoxy]-phenylamino}-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester, and3-Cyano-4-(4-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-phenoxy}-phenylamino)-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylicacid methyl ester, or a pharmaceutically acceptable salt thereof.
 2. Apharmaceutical composition comprising one or more compounds according toclaim 1 and one or more pharmaceutically acceptable carriers therefor.